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Regulated cell death pathways in doxorubicin-induced cardiotoxicity | Cell Death & Disease
<!DOCTYPE html> <html lang="en" class="grade-c"> <head> <title>Regulated cell death pathways in doxorubicin-induced cardiotoxicity | Cell Death & Disease</title> <link rel="alternate" type="application/rss+xml" href="https://www.nature.com/cddis.rss"/> <link rel="preconnect" href="https://cmp.nature.com" crossorigin> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width,initial-scale=1.0,maximum-scale=5,user-scalable=yes"> <meta name="360-site-verification" content="5a2dc4ab3fcb9b0393241ffbbb490480" /> <script data-test="dataLayer"> window.dataLayer = [{"content":{"category":{"contentType":"review article","legacy":{"webtrendsPrimaryArticleType":"reviews","webtrendsSubjectTerms":"cardiomyopathies;mechanisms-of-disease","webtrendsContentCategory":null,"webtrendsContentCollection":null,"webtrendsContentGroup":"Cell Death & Disease","webtrendsContentGroupType":null,"webtrendsContentSubGroup":"Review Article","status":null}},"article":{"doi":"10.1038/s41419-021-03614-x"},"attributes":{"cms":null,"deliveryPlatform":"oscar","copyright":{"open":true,"legacy":{"webtrendsLicenceType":"http://creativecommons.org/licenses/by/4.0/"}}},"contentInfo":{"authors":["Effimia Christidi","Liam R. 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The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. 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The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. 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data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2021-04-01">01 April 2021</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Regulated cell death pathways in doxorubicin-induced cardiotoxicity</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Effimia-Christidi-Aff1" data-author-popup="auth-Effimia-Christidi-Aff1" data-author-search="Christidi, Effimia">Effimia Christidi</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Liam_R_-Brunham-Aff1-Aff2-Aff3" data-author-popup="auth-Liam_R_-Brunham-Aff1-Aff2-Aff3" data-author-search="Brunham, Liam R." data-corresp-id="c1">Liam R. Brunham<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-3686-3807"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-3686-3807</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup> </li></ul> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/cddis" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Cell Death & Disease</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 12</b>, Article number: <span data-test="article-number">339</span> (<span data-test="article-publication-year">2021</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">25k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">10 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/s41419-021-03614-x/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/cardiomyopathies" data-track="click" data-track-action="view subject" data-track-label="link">Cardiomyopathies</a></li><li class="c-article-subject-list__subject"><a href="/subjects/mechanisms-of-disease" data-track="click" data-track-action="view subject" data-track-label="link">Mechanisms of disease</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.</p></div></div></section> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41401-023-01068-9/MediaObjects/41401_2023_1068_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41401-023-01068-9?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41401-023-01068-9">Regulated cell death pathways in cardiomyopathy </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">13 March 2023</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41420-023-01565-0/MediaObjects/41420_2023_1565_Figa_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41420-023-01565-0?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41420-023-01565-0">Nrf2: a dark horse in doxorubicin-induced cardiotoxicity </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">26 July 2023</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-020-68907-1/MediaObjects/41598_2020_68907_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-020-68907-1?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41598-020-68907-1">Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4 </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">21 July 2020</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1734503290, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Facts"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Facts</h2><div class="c-article-section__content" id="Sec1-content"><ul class="u-list-style-bullet"> <li> <p>Doxorubicin simultaneously triggers different regulated cell death (RCD) pathways.</p> </li> <li> <p>The role of apoptosis in doxorubicin induced cardiotoxicity (DIC) is well established, however new molecular players are constantly emerging.</p> </li> <li> <p>In recent years, emerging RCD pathways have been implicated in DIC including ferroptosis, necroptosis and pyroptosis.</p> </li> <li> <p>The role of autophagy remains unclear as to whether it has a protective or detrimental effect on doxorubicin response.</p> </li> <li> <p>Sirtuins protect from DIC and are involved in multiple RCDs.</p> </li> </ul></div></div></section><section data-title="Open questions"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Open questions</h2><div class="c-article-section__content" id="Sec2-content"><ul class="u-list-style-bullet"> <li> <p>What is the effect of genetic variants associated with DIC on regulated cell death?</p> </li> <li> <p>Which RCD pathway has the strongest effect on doxorubicin induced cardiotoxicity?</p> </li> <li> <p>Are there therapeutic agents that act upstream that can simultaneously block more than one RCD pathways?</p> </li> </ul></div></div></section><section data-title="Introduction"><div class="c-article-section" id="Sec3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec3">Introduction</h2><div class="c-article-section__content" id="Sec3-content"><p>Advancements in drug discovery have resulted in a significant increase in survivorship for patients with cancer<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Miller, K. D. et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69, 363–385 (2019)." href="/articles/s41419-021-03614-x#ref-CR1" id="ref-link-section-d83076274e444">1</a></sup>. However, many chemotherapy drugs cause adverse drug reactions with cardiovascular toxicity being one of the most common and life threatening<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Global Burden of Disease Cancer Collaboration GB of DC, Fitzmaurice, C. et al. The global burden of cancer 2013. JAMA Oncol. 1, 505–527 (2015)." href="/articles/s41419-021-03614-x#ref-CR2" id="ref-link-section-d83076274e448">2</a></sup>. Anthracyclines are a class of chemotherapeutic drugs administered in adult and pediatric patients for the treatment of malignancies such as lymphoma, sarcoma, breast cancer, and others<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Volkova, M. & Russell, R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 7, 214–220 (2012)." href="/articles/s41419-021-03614-x#ref-CR3" id="ref-link-section-d83076274e452">3</a></sup>. The most commonly used anthracycline is doxorubicin. However, despite its potency, up to a quarter of patients experience doxorubicin-induced cardiotoxicity (DIC), limiting the use of this agent<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Swain, S. M., Whaley, F. S. & Ewer, M. S. Congestive heart failure in patients treated with doxorubicin. Cancer 97, 2869–2879 (2003)." href="/articles/s41419-021-03614-x#ref-CR4" id="ref-link-section-d83076274e456">4</a></sup>. Clinically, DIC is characterized by a reduction in the left ventricular ejection fraction, an increase in the ventricular wall thickness, arrhythmia, and heart failure which can result in death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Volkova, M. & Russell, R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 7, 214–220 (2012)." href="/articles/s41419-021-03614-x#ref-CR3" id="ref-link-section-d83076274e460">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Lefrak, E. A., Piťha, J., Rosenheim, S. & Gottlieb, J. A. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32, 302–314 (1973)." href="/articles/s41419-021-03614-x#ref-CR5" id="ref-link-section-d83076274e463">5</a></sup>.</p><p>Despite extensive research on the mechanisms by which doxorubicin causes cardiotoxicity, the molecular pathogenesis of DIC remains incompletely understood<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Volkova, M. & Russell, R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 7, 214–220 (2012)." href="/articles/s41419-021-03614-x#ref-CR3" id="ref-link-section-d83076274e470">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Shi, Y., Moon, M., Dawood, S., McManus, B. & Liu, P. P. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36, 296–305 (2011)." href="/articles/s41419-021-03614-x#ref-CR6" id="ref-link-section-d83076274e473">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Zhang, S. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med 18, 1639–1642 (2012)." href="/articles/s41419-021-03614-x#ref-CR7" id="ref-link-section-d83076274e476">7</a></sup>. The three major sources of cell damage that lead to cardiomyocyte cell death are (1) excessive reactive oxygen species (ROS) production leading to damage to lipids, DNA and proteins; (2) TOP2B poisoning creating double-strand breaks; and (3) mitochondria damage<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Henriksen, P. A. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart 104, 971–977 (2018)." href="/articles/s41419-021-03614-x#ref-CR8" id="ref-link-section-d83076274e480">8</a></sup>.</p><p>Recently, novel regulated cell death (RCD) pathways have been described<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Tang, D., Kang, R., Vanden, BergheT., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019)." href="/articles/s41419-021-03614-x#ref-CR9" id="ref-link-section-d83076274e487">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018)." href="/articles/s41419-021-03614-x#ref-CR10" id="ref-link-section-d83076274e490">10</a></sup> and new research has emerged identifying the role of these pathways in DIC. Here we review recent discoveries of the role of RCD pathways in DIC in the context of autophagy, necroptosis, ferroptosis, pyroptosis, and apoptosis and we discuss how these findings have advanced our understanding of the molecular mechanisms underlying DIC.</p></div></div></section><section data-title="Regulated cell death"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Regulated cell death</h2><div class="c-article-section__content" id="Sec4-content"><p>Initially, cell death was considered a passive result of uncontrolled cellular damage. Subsequent discoveries led to the recognition that cells can die in a genetically and biochemically coordinated manner. In 1972, apoptosis—the first form of RCD—was described<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007)." href="/articles/s41419-021-03614-x#ref-CR11" id="ref-link-section-d83076274e502">11</a></sup>. There are now more than ten different types of RCD, defined as precise signaling pathways performed by distinct molecules with specific biochemical and functional consequences<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Tang, D., Kang, R., Vanden, BergheT., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019)." href="/articles/s41419-021-03614-x#ref-CR9" id="ref-link-section-d83076274e506">9</a></sup>. RCD differs from accidental, unregulated cell death (necrosis) which is triggered unexpectedly by cellular injury or attack and lacks controlled signaling mechanisms<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Tang, D., Kang, R., Vanden, BergheT., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019)." href="/articles/s41419-021-03614-x#ref-CR9" id="ref-link-section-d83076274e510">9</a></sup>. Doxorubicin can induce cardiomyocyte death via both regulated and unregulated cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Tang, D., Kang, R., Vanden, BergheT., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019)." href="/articles/s41419-021-03614-x#ref-CR9" id="ref-link-section-d83076274e514">9</a></sup>.</p></div></div></section><section data-title="Autophagy"><div class="c-article-section" id="Sec5-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec5">Autophagy</h2><div class="c-article-section__content" id="Sec5-content"><p>Macroautophagy (hereafter referred to as autophagy) is a homeostatic process by which cellular components are degraded and recycled under normal and stress conditions<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018)." href="/articles/s41419-021-03614-x#ref-CR12" id="ref-link-section-d83076274e526">12</a></sup>. Such cellular stress conditions are caused by doxorubicin and as might be expected autophagy may be activated during doxorubicin treatment. Indeed, doxorubicin can trigger autophagy, but it is the deregulation of autophagy that leads to excessive cardiomyocyte death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Bartlett J. J., Trivedi P., Pulinilkunnil T. Autophagic dysregulation in doxorubicin cardiomyopathy. J. Mol. Cell Cardiol. 104, 1–8 (2017)." href="/articles/s41419-021-03614-x#ref-CR13" id="ref-link-section-d83076274e530">13</a></sup>.</p><p>Autophagy begins with activation of the AMPK pathway and the inhibition of the mTOR pathway, which signals the budding of the pre-autophagosome from the endoplasmic reticulum and proceeds with the formation of an initiation complex consisting of Unc-51-like kinase 1 (ULK1), RB1-inducible coiled-coil protein 1 (FIP200), and autophagy-related gene (Atg) 13<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018)." href="/articles/s41419-021-03614-x#ref-CR14" id="ref-link-section-d83076274e537">14</a></sup>. Nucleation and recruitment of many tethering proteins then take places such as Beclin 1, which is then phosphorylated by ULK1, and which in turn activates vacuolar protein sorting 34 (Vps34) and Vps15. Vps 34-15 then recruits multiple Atg proteins and leads to the formation of the autophagosome<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018)." href="/articles/s41419-021-03614-x#ref-CR14" id="ref-link-section-d83076274e541">14</a></sup>. Subsequently, the autophagosome maturates and elongates. At this stage, LC3-I (microtubule-associated protein 1A/1B-light chain 3) a key protein in autophagosome biosynthesis becomes lipidated to form mature LC3-II and protein p62, a ubiquitin-binding cargo receptor, that sorts proteins, organelles, and other aggregates within the autophagosome<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018)." href="/articles/s41419-021-03614-x#ref-CR14" id="ref-link-section-d83076274e545">14</a></sup>. Finally, in the last step of autophagy, the autophagosome fuses with the lysosome, where proteases breakdown the autophagosome and its compartments, leading to the degradation or the recycling of damaged components<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Feng, Y., He, D., Yao, Z. & Klionsky, D. J. The machinery of macroautophagy. Cell Res. 24, 24–41 (2014)." href="/articles/s41419-021-03614-x#ref-CR15" id="ref-link-section-d83076274e549">15</a></sup>.</p><p>Whether doxorubicin induces or disrupts autophagy in cardiac tissue is controversial as studies examining the role of autophagy in DIC have reported conflicting evidence (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41419-021-03614-x#Tab1">1</a>). For example, in the initiation stage, studies report that doxorubicin upregulates AMPK<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wu, R. et al. Doxorubicin toxicity changes myocardial energy metabolism in rats. Chem. Biol. Interact. 244, 149–158 (2016)." href="#ref-CR16" id="ref-link-section-d83076274e559">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, X. et al. Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK. Biochem. Pharm. 88, 334–350 (2014)." href="#ref-CR17" id="ref-link-section-d83076274e559_1">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Pointon, A. V. et al. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS ONE 5, e12733 (2010)." href="#ref-CR18" id="ref-link-section-d83076274e559_2">18</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Lv, X. et al. Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS ONE 7, e47351 (2012)." href="#ref-CR19" id="ref-link-section-d83076274e559_3">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Chen M. et al. Activation of AMP-activated protein kinase contributes to doxorubicin-induced cell death and apoptosis in cultured myocardial H9c2 cells. Cell Biochem. Biophys. 60, 311–322 (2011)." href="/articles/s41419-021-03614-x#ref-CR20" id="ref-link-section-d83076274e562">20</a></sup>, while others showed no change<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Wu, R. et al. Doxorubicin toxicity changes myocardial energy metabolism in rats. Chem. Biol. Interact. 244, 149–158 (2016)." href="/articles/s41419-021-03614-x#ref-CR16" id="ref-link-section-d83076274e566">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Sun, A. et al. Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy. J. Mol. Cell Cardiol. 71, 92–104 (2014)." href="/articles/s41419-021-03614-x#ref-CR21" id="ref-link-section-d83076274e569">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Hong E. et al. Cardiac Expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice. Endocrinology 154, 3937–3946 (2013)." href="/articles/s41419-021-03614-x#ref-CR22" id="ref-link-section-d83076274e572">22</a></sup> or a decrease in AMPK activation<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Andreadou, I. et al. Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. J. Mol. Cell Cardiol. 69, 4–16 (2014)." href="#ref-CR23" id="ref-link-section-d83076274e576">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, S., Song, P. & Zou, M. H. Inhibition of AMP-activated protein kinase α (AMPKα) by doxorubicin accentuates genotoxic stress and cell death in mouse embryonic fibroblasts and cardiomyocytes: Role of p53 and SIRT1. J. Biol. Chem. 287, 8001–8012 (2012)." href="#ref-CR24" id="ref-link-section-d83076274e576_1">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Gu J. et al. Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity. Int. Immunopharmacol. 32, 1–7 (2016)." href="/articles/s41419-021-03614-x#ref-CR25" id="ref-link-section-d83076274e579">25</a></sup>. Similarly, pharmacologic or genetic inhibition of autophagy has yielded contradictory results with some studies reporting protection while others show that blockade of autophagy results in DIC attenuation (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41419-021-03614-x#Tab1">1</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Lv, X. et al. Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS ONE 7, e47351 (2012)." href="/articles/s41419-021-03614-x#ref-CR19" id="ref-link-section-d83076274e587">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Coelho, A. R. et al. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim. Biophys. Acta 1863, 2904–2923 (2017)." href="#ref-CR26" id="ref-link-section-d83076274e590">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wu, Y.-Z., Zhang, L., Wu, Z.-X., Shan, T. & Xiong, C. Berberine ameliorates doxorubicin-induced cardiotoxicity via a SIRT1/p66Shc-mediated pathway. Oxid. Med. Cell Longev. 2019, 1–14 (2019)." href="#ref-CR27" id="ref-link-section-d83076274e590_1">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Yu, S.-Y., Liu, L., Li, P. & Li, J. Rapamycin inhibits the mTOR/p70S6K pathway and attenuates cardiac fibrosis in adriamycin-induced dilated cardiomyopathy. Thorac. Cardiovasc. Surg. 61, 223–228 (2012)." href="#ref-CR28" id="ref-link-section-d83076274e590_2">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Park J. H. et al. Doxorubicin regulates autophagy signals via accumulation of cytosolic Ca2+ in human cardiac progenitor cells. Int. J. Mol. Sci. 17, 1680 (2016)." href="#ref-CR29" id="ref-link-section-d83076274e590_3">29</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e593">30</a></sup>.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Evidence of doxorubicin-induced autophagy in the heart.</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41419-021-03614-x/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Recent evidence has helped to resolve this apparent discrepancy by proposing that doxorubicin initially induces autophagy but then blocks it<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="#ref-CR30" id="ref-link-section-d83076274e1157">30</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Abdullah, C. S. et al. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration. Sci. Rep. 9, 2002 (2019)." href="#ref-CR31" id="ref-link-section-d83076274e1157_1">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dimitrakis, P., Romay-Ogando, M. I., Timolati, F., Suter, T. M. & Zuppinger, C. Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes. Cell Tissue Res. 350, 361–372 (2012)." href="#ref-CR32" id="ref-link-section-d83076274e1157_2">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1160">33</a></sup> resulting in the accumulation of undegraded autophagosomes and autolysosomes which exacerbate the damage in cardiomyocytes leading to their death (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig1">1</a>). Specifically, a low dose of doxorubicin resulted in LC3-II, p62, and Beclin1 protein expression increase, indicating induction of autophagy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e1167">30</a></sup>. However, when assessing downstream activities of autophagy, doxorubicin impaired the autophagic flux and inhibited lysosomal acidification in cardiomyocytes. This blockade in the autophagic process resulted in the accumulation of undegraded autolysosomes, which in turn leads to ROS production and DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e1171">30</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig1">1</a>). Mice haploinsufficient for Beclin 1 and therefore with reduced autophagy initiation capacity, had a reduced number of unprocessed autolysosomes compared to the wildtype mice upon doxorubicin treatment, and consequently, this lead to a decreased in ROS production and attenuation of DIC. Conversely, increasing the level of autophagy by Beclin 1 overexpression augments DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e1179">30</a></sup>. Similarly, doxorubicin inhibits transcription factor EB (TFEB) expression which in turn suppresses lysosomal proteolysis resulting in autolysosome accumulation and reduced viability<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1183">33</a></sup>. TFEB is a positive regulator of autophagy critically involved in autophagosomal processing and lysosomal integrity, function, and fusion<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1187">33</a></sup>. Genetic restoration and pharmacologic activation of TFEB using Torin-1 prevent doxorubicin-induced inhibition of cathepsin B a lysosomal cysteine protease and ROS production, resulting in increased cell viability<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1191">33</a></sup>. In summary, recent studies demonstrate that doxorubicin suppresses lysosomal proteolysis resulting in autophagosome and autolysosome accumulation promoting ROS production and cell death. In consequence, blocking autophagy initiation or stimulating lysosomal function serves as a potential therapeutic approach as it reduces the accumulation of autolysosomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Bartlett J. J., Trivedi P., Pulinilkunnil T. Autophagic dysregulation in doxorubicin cardiomyopathy. J. Mol. Cell Cardiol. 104, 1–8 (2017)." href="/articles/s41419-021-03614-x#ref-CR13" id="ref-link-section-d83076274e1195">13</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e1198">30</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Abdullah, C. S. et al. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration. Sci. Rep. 9, 2002 (2019)." href="/articles/s41419-021-03614-x#ref-CR31" id="ref-link-section-d83076274e1201">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1204">33</a></sup> and attenuates ROS production.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Role of doxorubicin in autophagy-related cardiomyocyte death."><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1: Role of doxorubicin in autophagy-related cardiomyocyte death.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="455"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Schematic representation of autophagy during doxorubicin treatment. Doxorubicin disrupts autophagy by: inducing initiation through AMPK activation and/or mTOR inhibition, the formation of the phagophore, upregulation of Atg proteins, and by blocking lysosomal proteolysis resulting in accumulation of autophagosomes and autolysosomes and reactive oxygen species. DOX doxorubicin, AMPK 5′ AMP-activated protein kinase, mTOR mammalian target of rapamycin, TFEB transcription factor EB, Atg autophagy-related protein, LC3II microtubule-associated protein 1A/1B-light chain 3, ROS reactive oxygen species.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>These findings may explain in part the discrepant results obtained in assessing the effect of doxorubicin in autophagy. Doxorubicin has an opposite effect on early (autophagy induction) vs. later stages of autophagy (autophagy blockade)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="#ref-CR30" id="ref-link-section-d83076274e1231">30</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Abdullah, C. S. et al. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration. Sci. Rep. 9, 2002 (2019)." href="#ref-CR31" id="ref-link-section-d83076274e1231_1">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dimitrakis, P., Romay-Ogando, M. I., Timolati, F., Suter, T. M. & Zuppinger, C. Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes. Cell Tissue Res. 350, 361–372 (2012)." href="#ref-CR32" id="ref-link-section-d83076274e1231_2">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Bartlett, J. J., Trivedi, P. C., Yeung, P., Kienesberger, P. C. & Pulinilkunnil, T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem. J. 473, 3769–3789 (2016)." href="/articles/s41419-021-03614-x#ref-CR33" id="ref-link-section-d83076274e1234">33</a></sup> and as a result, assessing doxorubicin’s effect on autophagy could generate a different outcome depending on which stage of autophagy is being evaluated. Differences in experimental settings including in vitro vs. in vivo models, different doxorubicin doses, different duration of treatments, as well as cross-sectional vs. longitudinal measurements could also give rise to the discrepancies seen in the literature<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Bartlett J. J., Trivedi P., Pulinilkunnil T. Autophagic dysregulation in doxorubicin cardiomyopathy. J. Mol. Cell Cardiol. 104, 1–8 (2017)." href="/articles/s41419-021-03614-x#ref-CR13" id="ref-link-section-d83076274e1238">13</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Li, D. L. et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687 (2016)." href="/articles/s41419-021-03614-x#ref-CR30" id="ref-link-section-d83076274e1241">30</a></sup>.</p><p>On the other hand, research examining the effect of autophagy <i>prior</i> to doxorubicin treatment is in agreement and shows protection from DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hall, S. E., Smuder, A. J. & Hayward, R. Effects of calorie restriction and voluntary exercise on doxorubicin-induced cardiotoxicity. Integr. Cancer Ther. 18, 153473541984399 (2019)." href="#ref-CR34" id="ref-link-section-d83076274e1251">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dutta, D., Xu, J., Dirain, M. L. S. & Leeuwenburgh, C. Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity. Free Radic. Biol. Med. 74, 252–262 (2014)." href="#ref-CR35" id="ref-link-section-d83076274e1251_1">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mitra, M. S., Donthamsetty, S., White, B., Latendresse, J. R. & Mehendale, H. M. Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. Toxicol. Appl. Pharm. 225, 90–101 (2007)." href="#ref-CR36" id="ref-link-section-d83076274e1251_2">36</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kawaguchi, T. et al. Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res. 96, 456–465 (2012)." href="#ref-CR37" id="ref-link-section-d83076274e1251_3">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Xu, X. et al. Macrophage migration inhibitory factor (MIF) deficiency exacerbates aging-induced cardiac remodeling and dysfunction despite improved inflammation: role of autophagy regulation. Sci. Rep. 6, 22488 (2016)." href="/articles/s41419-021-03614-x#ref-CR38" id="ref-link-section-d83076274e1254">38</a></sup>. Stimulating autophagy prior to doxorubicin treatment by mTOR inhibition via rapamycin treatment or by caloric restriction results in improved cardiac outcomes and reduced lethality in rodents models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hall, S. E., Smuder, A. J. & Hayward, R. Effects of calorie restriction and voluntary exercise on doxorubicin-induced cardiotoxicity. Integr. Cancer Ther. 18, 153473541984399 (2019)." href="#ref-CR34" id="ref-link-section-d83076274e1258">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dutta, D., Xu, J., Dirain, M. L. S. & Leeuwenburgh, C. Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity. Free Radic. Biol. Med. 74, 252–262 (2014)." href="#ref-CR35" id="ref-link-section-d83076274e1258_1">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mitra, M. S., Donthamsetty, S., White, B., Latendresse, J. R. & Mehendale, H. M. Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. Toxicol. Appl. Pharm. 225, 90–101 (2007)." href="#ref-CR36" id="ref-link-section-d83076274e1258_2">36</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kawaguchi, T. et al. Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res. 96, 456–465 (2012)." href="#ref-CR37" id="ref-link-section-d83076274e1258_3">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Xu, X. et al. Macrophage migration inhibitory factor (MIF) deficiency exacerbates aging-induced cardiac remodeling and dysfunction despite improved inflammation: role of autophagy regulation. Sci. Rep. 6, 22488 (2016)." href="/articles/s41419-021-03614-x#ref-CR38" id="ref-link-section-d83076274e1261">38</a></sup>. A possible explanation for this is that induction of autophagy prior to doxorubicin treatment may render cells better able to tolerate the cellular stress of doxorubicin by eliminating damaged cellular components.</p></div></div></section><section data-title="Ferroptosis"><div class="c-article-section" id="Sec6-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec6">Ferroptosis</h2><div class="c-article-section__content" id="Sec6-content"><p>Ferroptosis, another pathway by which doxorubicin exerts its cardiotoxic effect, is an RCD pathway characterized by the iron-dependent accumulation of lipid peroxides<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012)." href="/articles/s41419-021-03614-x#ref-CR39" id="ref-link-section-d83076274e1274">39</a></sup>. Lipid peroxides are one of the many sources of ROS involved in DIC and the role of iron in DIC is been well characterized<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Shi, Y., Moon, M., Dawood, S., McManus, B. & Liu, P. P. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36, 296–305 (2011)." href="/articles/s41419-021-03614-x#ref-CR6" id="ref-link-section-d83076274e1278">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Xu, X., Persson, H. L. & Richardson, D. R. Molecular pharmacology of the interaction of anthracyclines with iron. Mol. Pharm. 68, 261–271 (2005)." href="/articles/s41419-021-03614-x#ref-CR40" id="ref-link-section-d83076274e1281">40</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P. & Cairo, G. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61, 8422–8428 (2001)." href="/articles/s41419-021-03614-x#ref-CR41" id="ref-link-section-d83076274e1284">41</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig2">2</a>). Doxorubicin treatment increases the labile iron pool in cells which is toxic<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Xu, X., Persson, H. L. & Richardson, D. R. Molecular pharmacology of the interaction of anthracyclines with iron. Mol. Pharm. 68, 261–271 (2005)." href="/articles/s41419-021-03614-x#ref-CR40" id="ref-link-section-d83076274e1291">40</a></sup>. In line with this, rats fed an iron-rich diet and treated with doxorubicin have worse cardiac outcomes than rats fed a control diet<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Panjrath, G. S. et al. Potentiation of doxorubicin cardiotoxicity by iron loading in a rodent model. J. Am. Coll. Cardiol. 49, 2457–2464 (2007)." href="/articles/s41419-021-03614-x#ref-CR42" id="ref-link-section-d83076274e1295">42</a></sup>. Doxorubicin and its metabolites can affect iron homeostasis by inactivating iron regulatory proteins 1 and 2 (IRP1 and IRP2)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P. & Cairo, G. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61, 8422–8428 (2001)." href="/articles/s41419-021-03614-x#ref-CR41" id="ref-link-section-d83076274e1300">41</a></sup>. Inactive IRPs bind to iron-response elements (IREs) modifying the expression of genes involved in iron metabolism<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P. & Cairo, G. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61, 8422–8428 (2001)." href="/articles/s41419-021-03614-x#ref-CR41" id="ref-link-section-d83076274e1304">41</a></sup>. Doxorubicin disrupts the mRNA of ferritin’s IRE, leading to reduced ferritin and increased labile iron<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Canzoneri, J. C. & Oyelere, A. K. Interaction of anthracyclines with iron responsive element mRNAs. Nucleic Acids Res. 36, 6825–6834 (2008)." href="/articles/s41419-021-03614-x#ref-CR43" id="ref-link-section-d83076274e1308">43</a></sup>. Similarly, doxorubicin upregulates TfR allowing more iron to enter the cell leading to excess free intracellular iron<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Kotamraju, S., Chitambar, C. R., Kalivendi, S. V., Joseph, J. & Kalyanaraman, B. Transferrin receptor-dependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells. J. Biol. Chem. 277, 17179–17187 (2002)." href="/articles/s41419-021-03614-x#ref-CR44" id="ref-link-section-d83076274e1312">44</a></sup>. Conversely, inhibition of TfR with an anti-TfR antibody reduces iron uptake and leads to reduced intracellular oxidant formation and cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Kotamraju, S., Chitambar, C. R., Kalivendi, S. V., Joseph, J. & Kalyanaraman, B. Transferrin receptor-dependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells. J. Biol. Chem. 277, 17179–17187 (2002)." href="/articles/s41419-021-03614-x#ref-CR44" id="ref-link-section-d83076274e1316">44</a></sup>. In addition, humans with mutations in the human hemochromatosis protein (HFE)—which controls the interaction of TfR with transferrin—experience iron overload in different tissues including the heart. Based on this, mutations in the HFE gene were hypothesized to make patients more susceptible to DIC and two variants in the HFE gene have been associated with increased susceptibility to DIC; a finding not replicated in all studies<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Linschoten, M., Teske, A. J., Cramer, M. J., van der Wall, E. & Asselbergs, F. W. Chemotherapy-related cardiac dysfunction. Circ. Genom. Precis. Med. 11, e001753 (2018)." href="#ref-CR45" id="ref-link-section-d83076274e1320">45</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Armenian, S. H. et al. Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br. J. Haematol. 163, 205–213 (2013)." href="#ref-CR46" id="ref-link-section-d83076274e1320_1">46</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Leger, K. J. et al. Clinical and genetic determinants of cardiomyopathy risk among hematopoietic cell transplantation survivors. Biol. Blood Marrow Transpl. 22, 1094–1101 (2016)." href="#ref-CR47" id="ref-link-section-d83076274e1320_2">47</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Lipshultz, S. E. et al. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 119, 3555–3562 (2013)." href="/articles/s41419-021-03614-x#ref-CR48" id="ref-link-section-d83076274e1323">48</a></sup>. Deletion of the HFE protein in mice results in excess free iron and increased susceptibility to DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Miranda, C. J. et al. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102, 2574–2580 (2003)." href="/articles/s41419-021-03614-x#ref-CR49" id="ref-link-section-d83076274e1328">49</a></sup>. Finally, the importance of iron overload in the heart during doxorubicin treatment is highlighted by the clinical use of the iron chelator dexrazoxane, the only clinically approved cardioprotection.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Doxorubicin-induced ferroptosis."><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2: Doxorubicin-induced ferroptosis.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="461"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Schematic representation of doxorubicin-induced ferroptosis pathway. Doxorubicin treatment results in iron overload through upregulation of TfR and inactivation of ferritin. Free iron complexes with doxorubicin and through the Fenton reaction create reactive oxygen species (ROS). Doxorubicin induces lipid peroxidation by inhibiting cytosolic and mitochondrial GPX4 resulting in ferroptosis. In the mitochondria, doxorubicin causes iron overload by blocking MitoFer and ABCB8. In the nucleus, activation of NRF2 results in upregulation of HMOX1 leading to heme degradation and resulting in excess free iron and ferroptosis. Tf transferrin, TfR transferrin receptor, IRP iron response regulatory protein, IRE Iron response element, NRF2 nuclear factor erythroid 2-related factor, HMOX1 heme oxygenase 1, PUFA polyunsaturated fatty acids, Lipid-OO lipid peroxides, GSH reduced glutathione, GPX4 glutathione peroxidase, GSSG glutathione disulfide, H<sub>2</sub>O<sub>2</sub> oxygen peroxide, MitoFer mitochondria ferritin. ABCB8 ATP-binding cassette sub-family B member 8, ROS reactive oxygen species.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Mitochondrial iron overload is a central underlying mechanism of DIC. Heart biopsy specimens from patients with heart failure due to DIC show excess iron in their mitochondria compared to the hearts from other non-DIC heart failure patients or healthy individuals<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Ichikawa, Y. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Investig. 124, 617–630 (2014)." href="/articles/s41419-021-03614-x#ref-CR50" id="ref-link-section-d83076274e1359">50</a></sup>. Excess iron in the mitochondrial could be explained by doxorubicin-induced downregulation of ABCB8 protein that controls iron export from the mitochondria<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Ichikawa, Y. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Investig. 124, 617–630 (2014)." href="/articles/s41419-021-03614-x#ref-CR50" id="ref-link-section-d83076274e1363">50</a></sup>. Another protein that is important in mitochondria iron homeostasis is mitochondrial ferritin (MitoFer), which, similar to its cytoplasmic equivalent, stores free iron<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Maccarinelli, F. et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity. J. Mol. Med. 92, 859–869 (2014)." href="/articles/s41419-021-03614-x#ref-CR51" id="ref-link-section-d83076274e1367">51</a></sup>. Genetic inactivation of MitoFer in rodents results in increased DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Maccarinelli, F. et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity. J. Mol. Med. 92, 859–869 (2014)." href="/articles/s41419-021-03614-x#ref-CR51" id="ref-link-section-d83076274e1371">51</a></sup>.</p><p>Recent understanding of ferroptosis helps to explain in part the long-recognized role of abnormal iron homeostasis in DIC and provides new targets for preventative therapies (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig2">2</a>). Mice administered doxorubicin and ferrostatin-1, a ferroptosis inhibitor, have improved survival<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1381">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Liu, Y. et al. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. Cell Death Dis. 11, 756 (2020)." href="/articles/s41419-021-03614-x#ref-CR53" id="ref-link-section-d83076274e1384">53</a></sup>. The effect of ferrostatin-1 appears to be superior to agents that inhibit other RCD pathways including apoptosis and necroptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1388">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1391">54</a></sup>. Doxorubicin triggers ferroptosis in mice via the activation of nuclear factor erythroid 2-related factor 2 (<i>nrf-2</i>) which leads to the upregulation of heme oxygenase 1 (<i>hmox1</i>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1402">52</a></sup>. Hmox1 catalyzes heme degradation inducing the release of free iron and ultimately leading to the accumulation of oxidized lipids in the mitochondria membrane. In addition, doxorubicin downregulates a key anti-ferroptotic protein, glutathione peroxidase 4 (GPX4) in the cytosol and mitochondria and induces excessive lipid peroxidation through doxorubicin–Fe<sup>2+</sup> complex in the mitochondria<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1408">54</a></sup>. These findings highlight the importance of ferroptotic death in DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="#ref-CR52" id="ref-link-section-d83076274e1412">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Liu, Y. et al. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. Cell Death Dis. 11, 756 (2020)." href="#ref-CR53" id="ref-link-section-d83076274e1412_1">53</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1415">54</a></sup> and the crucial role that mitochondria play in doxorubicin-induced ferroptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1419">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1422">54</a></sup>. Agents such as MitoTempo, a mitochondrial anti-oxidant that completely blocked ferroptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1426">52</a></sup> and ferrostatin-1 could be promising cardioprotectants to blunt the cardiotoxic effects of doxorubicin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="#ref-CR52" id="ref-link-section-d83076274e1431">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Liu, Y. et al. Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition. Cell Death Dis. 11, 756 (2020)." href="#ref-CR53" id="ref-link-section-d83076274e1431_1">53</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1434">54</a></sup>.</p></div></div></section><section data-title="Necroptosis"><div class="c-article-section" id="Sec7-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec7">Necroptosis</h2><div class="c-article-section__content" id="Sec7-content"><p>Doxorubicin also activates another form of cell death, necroptosis (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig3">3</a>). Necroptosis is a regulated form of necrosis that involves the release of death-signaling cytokines<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014)." href="/articles/s41419-021-03614-x#ref-CR55" id="ref-link-section-d83076274e1449">55</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Choi M. E., Price D. R., Ryter S. W., Choi A. M. K. Necroptosis: Aa crucial pathogenic mediator of human disease. JCI Insight. 4, e128834 (2019)." href="/articles/s41419-021-03614-x#ref-CR56" id="ref-link-section-d83076274e1452">56</a></sup>. Mechanistically, tumor necrosis factor-α (TNF-α) activates the protein TNFR-associated death protein (TRADD) through TRFR1 and phosphorylates receptor-interacting serine/threonine-protein kinase 1(RIPK1) which recruits and phosphorylates RIPK3 forming the necroptosome<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014)." href="/articles/s41419-021-03614-x#ref-CR55" id="ref-link-section-d83076274e1456">55</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Choi M. E., Price D. R., Ryter S. W., Choi A. M. K. Necroptosis: Aa crucial pathogenic mediator of human disease. JCI Insight. 4, e128834 (2019)." href="/articles/s41419-021-03614-x#ref-CR56" id="ref-link-section-d83076274e1459">56</a></sup>. The necroptosome subsequently phosphorylates the mixed lineage kinase domain-like protein (MLK1) which ruptures the plasma membrane and allows the release of organelles and inflammatory factors inducing an immune response and leading to cell demise<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Linkermann, A. & Green, D. R. Necroptosis. N. Engl. J. Med. 370, 455–465 (2014)." href="/articles/s41419-021-03614-x#ref-CR55" id="ref-link-section-d83076274e1463">55</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Doxorubicin-induced necroptosis."><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3: Doxorubicin-induced necroptosis.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="601"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Schematic representation of the doxorubicin-induced necroptosis pathway. Doxorubicin causes upregulation of TNFα, activating TRADD and FADD, and upon caspase 8 inhibition and activation of RIPK1, RIPK3, and MLKL induces cell death via necroptosis. Doxorubicin can also activate necroptosis via the RIPK1 independent pathway, where RIPK3 activates CAMKII and mitochondrial permeability transition pore (mPTP) resulting in membrane potential and integrity loss. TNFα tumor necrosis factor-alpha, TRADD tumor necrosis factor receptor type 1 associated death domain protein, FADD Fas-associated protein with death domain, RIPK receptor-interacting serine/threonine-protein kinase, CAMKII calcium/calmodulin-dependent protein kinase II association domain, MLKL mixed lineage kinase domain-like, mPTP mitochondrial permeability transition pore.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Left ventricular samples from end-stage heart failure patients have increased expression of necroptotic proteins, suggesting a role for necrotptosis in heart failure<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Szobi, A. et al. Analysis of necroptotic proteins in failing human hearts. J. Transl. Med. 15, 86 (2017)." href="/articles/s41419-021-03614-x#ref-CR57" id="ref-link-section-d83076274e1489">57</a></sup>. In DIC specifically, necrostatin-1 has a protective effect in vitro, while dexrazoxane during doxorubicin treatment is both able to downregulate apoptosis and necroptosis suggesting the involvement of both pathways in the pathogenesis of DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Yu, X. et al. Dexrazoxane ameliorates doxorubicin-induced cardiotoxicity by inhibiting both apoptosis and necroptosis in cardiomyocytes. Biochem. Biophys. Res. Commun. 523, 140–146 (2020)." href="/articles/s41419-021-03614-x#ref-CR58" id="ref-link-section-d83076274e1493">58</a></sup>. In addition, doxorubicin activates necroptosis through an alternative and novel necroptotic pathway, which together with necrosis causes more cell death than apoptosis (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig3">3</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016)." href="/articles/s41419-021-03614-x#ref-CR59" id="ref-link-section-d83076274e1500">59</a></sup>. Doxorubicin upregulates RIPK3 which binds and phosphorylates calmodulin kinase II (CaMKII) which in turn regulates the opening of the mitochondrial permeability transition pore (mPTP) leading to necroptosis and apoptosis. Evidently, necroptosis can occur in the absence of RIPK1 and MLKL<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016)." href="/articles/s41419-021-03614-x#ref-CR59" id="ref-link-section-d83076274e1504">59</a></sup>. The characterization of the exact players in doxorubicin-induced necroptosis will allow the identification of novel agents that may block this pathway. To date, necrostatin-1 and KN-93, a CAMKII inhibitor, have shown protection from DIC in experimental models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Yu, X. et al. Dexrazoxane ameliorates doxorubicin-induced cardiotoxicity by inhibiting both apoptosis and necroptosis in cardiomyocytes. Biochem. Biophys. Res. Commun. 523, 140–146 (2020)." href="/articles/s41419-021-03614-x#ref-CR58" id="ref-link-section-d83076274e1509">58</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016)." href="/articles/s41419-021-03614-x#ref-CR59" id="ref-link-section-d83076274e1512">59</a></sup>.</p></div></div></section><section data-title="Pyroptosis"><div class="c-article-section" id="Sec8-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec8">Pyroptosis</h2><div class="c-article-section__content" id="Sec8-content"><p>Pyroptosis was first demonstrated in 2001<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001)." href="/articles/s41419-021-03614-x#ref-CR60" id="ref-link-section-d83076274e1524">60</a></sup> and is now widely recognized to play a crucial role in the pathogenesis of cardiovascular diseases<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Jia, C. et al. Role of pyroptosis in cardiovascular diseases. Int. Immunopharmacol. 67, 311–318 (2019)." href="/articles/s41419-021-03614-x#ref-CR61" id="ref-link-section-d83076274e1528">61</a></sup>. Pyroptosis is characterized by increased inflammation and activation of caspase -1, caspase-3, caspase-4, and caspase-11 as well as NLR family pyrin domain containing 3 (NLRP3) leading to the cleavage of Gasdermin D (GSDMD) or GSDME and to the rupture of the plasma membrane that allows the release of interleukin-1beta (IL-1β) and IL-18<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015)." href="#ref-CR62" id="ref-link-section-d83076274e1532">62</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Man, S. M., Karki, R. & Kanneganti, T. D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 277, 61–75 (2017)." href="#ref-CR63" id="ref-link-section-d83076274e1532_1">63</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Ma, W., Wei, S., Zhang, B. & Li, W. Molecular mechanisms of cardiomyocyte death in drug-induced cardiotoxicity. Front. Cell Dev. Biol. 8, 434 (2020)." href="/articles/s41419-021-03614-x#ref-CR64" id="ref-link-section-d83076274e1535">64</a></sup>.</p><p>Doxorubicin-induced pyroptosis proceeds via the upregulation of Terminal Differentiation-Induced Non-Coding RNA (TINCR), which recruits IGF2BP and increases the expression of NLRP3 leading to activation of caspase-1, the cleavage of GMDSD-N, and the release of IL-1β, IL-18<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Meng, L. et al. Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J. Mol. Cell Cardiol. 136, 15–26 (2019)." href="/articles/s41419-021-03614-x#ref-CR65" id="ref-link-section-d83076274e1542">65</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig4">4</a>). The inhibition of NLRP3 using MCC950 protected the cells from doxorubicin-induced cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Meng, L. et al. Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J. Mol. Cell Cardiol. 136, 15–26 (2019)." href="/articles/s41419-021-03614-x#ref-CR65" id="ref-link-section-d83076274e1549">65</a></sup>. A different pathway by which doxorubicin triggers pyroptosis that acts through the activation of Bnip3 in the mitochondria has also been demonstrated<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Zheng, X. et al. Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life Sci. 242, 117186 (2020)." href="/articles/s41419-021-03614-x#ref-CR66" id="ref-link-section-d83076274e1553">66</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig4">4</a>). Doxorubicin increases the expression of BH3-only protein Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) which in turn activates caspase 3 and causes GSDME-dependent pyroptosis. Disruption of GSDME and silencing of Bnip3 protects cardiomyocytes from DIC in vitro<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Zheng, X. et al. Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life Sci. 242, 117186 (2020)." href="/articles/s41419-021-03614-x#ref-CR66" id="ref-link-section-d83076274e1561">66</a></sup>. Protection from DIC has also been shown to occur through the NLRP3/caspase 1signalling blockade using embryonic stem cell-derived exosomes, overexpression of heat shock protein 22, and pharmacologic inhibition of NLRP3<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Tavakoli Dargani, Z. & Singla, D. K. Embryonic stem cell-derived exosomes inhibit doxorubicin-induced TLR4-NLRP3-mediated cell death-pyroptosis. Am. J. Physiol. Circ. Physiol. 317, H460–H471 (2019)." href="#ref-CR67" id="ref-link-section-d83076274e1565">67</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Lan, Y., Wang, Y., Huang, K. & Zeng, Q. Heat shock protein 22 attenuates doxorubicin-induced cardiotoxicity via regulating inflammation and apoptosis. Front. Pharm. 11, 257 (2020)." href="#ref-CR68" id="ref-link-section-d83076274e1565_1">68</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Marchetti, C. et al. Pharmacologic inhibition of the NLRP3 inflammasome preserves cardiac function after ischemic and non-ischemic injury in the mouse. J. Cardiovasc. Pharm. 66, 1 (2015)." href="/articles/s41419-021-03614-x#ref-CR69" id="ref-link-section-d83076274e1568">69</a></sup>. Sirtuin 1 activation inhibits NLRP3 and protects cardiomyocytes from doxorubicin-induced pyroptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Sun, Z. et al. Dihydromyricetin alleviates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome through activation of SIRT1. Biochem. Pharm. 175, 113888 (2020)." href="/articles/s41419-021-03614-x#ref-CR70" id="ref-link-section-d83076274e1572">70</a></sup>. Inhibition of pyroptosis-related molecules, such as NLRP3, caspase 1, Bnip3, may represent a strategy to limit DIC.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Doxorubicin-induced pyroptosis."><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4: Doxorubicin-induced pyroptosis.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig4_HTML.png?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig4_HTML.png" alt="figure 4" loading="lazy" width="685" height="469"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>Schematic representation of doxorubicin-induced pyroptosis in the heart. Doxorubicin induces pyroptosis via the upregulation of TINCR, which recruits IGF2BP and increases the expression of NLRP3 leading to activation of caspase-1, the cleavage of GMDSD-N and the release of IL-1β, IL-18. Pyroptosis is also induced via BNIP3 activation in the mitochondria, which activates caspase 3 and causes GSDME-dependent pyroptosis. Sirtuin 1 activation inhibits NLRP3 and protects cardiomyocytes from doxorubicin-induced pyroptosis. BNIP3 BCL2 interacting protein 3, GSDMD gasdermin D, GSDME gasdermin E, TINCR terminal differentiation-induced NcRNA, IGF2BP1 insulin-like growth factor 2 mRNA-binding protein 1, NLRP3 NOD−, LRR−, and pyrin domain-containing protein 3, IL interleukin.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Apoptosis"><div class="c-article-section" id="Sec9-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec9">Apoptosis</h2><div class="c-article-section__content" id="Sec9-content"><p>The apoptotic pathway is the most well-characterized programmed cell death pathway and is the most studied in DIC. In summary, doxorubicin treatment causes excess oxidative stress (lipid peroxidates, doxorubicin’s reduced semiquinone moiety, charged doxorubicin iron complex, respiratory chain failure, peroxynitrites, and others) and mitochondrial damage which triggers cell death pathways including apoptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Shi, Y., Moon, M., Dawood, S., McManus, B. & Liu, P. P. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36, 296–305 (2011)." href="/articles/s41419-021-03614-x#ref-CR6" id="ref-link-section-d83076274e1603">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wenningmann N., Knapp M., Ande A., Vaidya T., Ait-Oudhia S. Insights into doxorubicin-induced cardiotoxicity: molecular mechanisms, preventive strategies, and early monitoring. Mol. Pharmacol. 96, 219–232 (2019)." href="#ref-CR71" id="ref-link-section-d83076274e1606">71</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Shi, J., Abdelwahid, E. & Wei, L. Apoptosis in anthracycline cardiomyopathy. Curr. Pediatr. Rev. 7, 329–336 (2011)." href="#ref-CR72" id="ref-link-section-d83076274e1606_1">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Fogli, S., Nieri, P., Cristina & Breschi, M. The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 18, 664–675 (2004)." href="/articles/s41419-021-03614-x#ref-CR73" id="ref-link-section-d83076274e1609">73</a></sup>. These events activate the intrinsic pathway and together with mitochondrial calcium overload induce the mPTP, resulting in mitochondrial membrane potential loss, mitochondrial swelling, and outer membrane rupture which eventually leads to the release of endonuclease G (EndoG), cytochrome c, and apoptosis-inducing factor (AIF) in the cytosol<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Shi, J., Abdelwahid, E. & Wei, L. Apoptosis in anthracycline cardiomyopathy. Curr. Pediatr. Rev. 7, 329–336 (2011)." href="/articles/s41419-021-03614-x#ref-CR72" id="ref-link-section-d83076274e1613">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Wallace K. B. Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc. Toxicol. 7, 101–107 (2007)." href="/articles/s41419-021-03614-x#ref-CR74" id="ref-link-section-d83076274e1616">74</a></sup>. Once in the cytosol, cytochrome c complexes with the adapter protein Apaf-1, dATP, and caspase 9 forming the apoptosome. Apoptosome formation leads to the cleavage and activation of caspase 9, which in turn cleaves and activates caspase 3 resulting in cell death. Doxorubicin can activate the intrinsic apoptosis pathway via Bax/Bak activation and translocation from the cytosol to the outer membrane of mitochondria inducing the mitochondrial outer membrane permeabilization, allowing the diffusion of several proteins to the cytoplasm including strong pro-apoptosis factor cytochrome c<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="An, J., Li, P., Li, J., Dietz, R. & Donath, S. ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity. J. Mol. Med. 87, 401–410 (2009)." href="/articles/s41419-021-03614-x#ref-CR75" id="ref-link-section-d83076274e1620">75</a></sup>. Doxorubicin activates intrinsic apoptosis by a number of mechanisms, including upregulation of p53 which leads to Bax upregulation<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="L’Ecuyer T. et al. DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am. J. Physiol. 291, H1273–H1280 (2006)." href="/articles/s41419-021-03614-x#ref-CR76" id="ref-link-section-d83076274e1624">76</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Shizukuda, Y., Matoba, S., Mian, O. Y., Nguyen, T. & Hwang, P. M. Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice. Mol. Cell Biochem. 273, 25–32 (2005)." href="/articles/s41419-021-03614-x#ref-CR77" id="ref-link-section-d83076274e1627">77</a></sup>, downregulation of GATA4 which decreases antiapoptotic Bcl-XL expression<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="Aries, A., Paradis, P., Lefebvre, C., Schwartz, R. J. & Nemer, M. Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity. Proc. Natl Acad. Sci. USA 101, 6975–6980 (2004)." href="/articles/s41419-021-03614-x#ref-CR78" id="ref-link-section-d83076274e1631">78</a></sup>, activation of JNK and MAPK, and inactivation PI-3K/Akt pro-survival pathway<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P. & Cairo, G. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61, 8422–8428 (2001)." href="/articles/s41419-021-03614-x#ref-CR41" id="ref-link-section-d83076274e1636">41</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Shi, J., Abdelwahid, E. & Wei, L. Apoptosis in anthracycline cardiomyopathy. Curr. Pediatr. Rev. 7, 329–336 (2011)." href="/articles/s41419-021-03614-x#ref-CR72" id="ref-link-section-d83076274e1639">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Fan, G. C. et al. Heat shock protein 20 interacting with phosphorylated akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity. Circ. Res. 103, 1270–1279 (2008)." href="#ref-CR79" id="ref-link-section-d83076274e1642">79</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Fukazawa, R. et al. Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. J. Mol. Cell Cardiol. 35, 1473–1479 (2003)." href="#ref-CR80" id="ref-link-section-d83076274e1642_1">80</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Das, J., Ghosh, J., Manna, P. & Sil, P. C. Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem. Pharm. 81, 891–909 (2011)." href="#ref-CR81" id="ref-link-section-d83076274e1642_2">81</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="d’Anglemont de Tassigny, A., Berdeaux, A., Souktani, R., Henry, P. & Ghaleh, B. The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2. Eur. J. Heart Fail. 10, 39–46 (2008)." href="/articles/s41419-021-03614-x#ref-CR82" id="ref-link-section-d83076274e1645">82</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig5">5</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Doxorubicin-induced apoptosis."><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 5: Doxorubicin-induced apoptosis.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig5_HTML.png?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig5_HTML.png" alt="figure 5" loading="lazy" width="685" height="544"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>Schematic representation of doxorubicin-induced apoptosis in the heart. Doxorubicin-induced upregulation of p53, Bax/Bak, and downregulation of GATA4 and Bcl-XL activating caspases 9, 3, and 7 resulting in apoptotic death. Mitochondrial calcium overload and activation of mitochondrial permeability transition pore (mPTP) lead to mitochondrial membrane potential loss, mitochondrial swelling, and outer membrane rupture allowing the release of endonuclease G (EndoG), cytochrome c and activation of caspase 9. Doxorubicin induces the extrinsic apoptotic pathway via the upregulation of death receptors and the activation of NFAT and NF-κΒ. DR: death receptor, TNFR1 tumor necrosis factor receptor 1, FADD Fas-associated protein with death domain, DR death receptor, lipid-OO lipid peroxides, EndoG endonuclease G, Ca2+ calcium, ROS reactive oxygen species, mPTP mitochondrial permeability transition pore, MOMP mitochondria outer membrane permeability, DOX doxorubicin, Bax Bcl-2-associated X protein, Apf-1 apoptosis protease factor-1, BID BH3 interacting-domain death, NF-κΒ nuclear factor-κB, NFAT4 nuclear factor of activated T-cells, GATA4 GATA-binding protein 4.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Doxorubicin also induces the extrinsic apoptotic pathway in cardiomyocytes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Nakamura, T. et al. Fas-mediated apoptosis in Adriamycin-induced cardiomyopathy in rats: in vivo study. Circulation 102, 572–578 (2000)." href="/articles/s41419-021-03614-x#ref-CR83" id="ref-link-section-d83076274e1674">83</a></sup>. Death ligands, such as FasL and TNFα, bind to their receptors and trigger the recruitment of cytosolic proteins Fas-associated via death domain (FADD) and TNFR-associated death domain (TRADD)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Shi, J., Abdelwahid, E. & Wei, L. Apoptosis in anthracycline cardiomyopathy. Curr. Pediatr. Rev. 7, 329–336 (2011)." href="/articles/s41419-021-03614-x#ref-CR72" id="ref-link-section-d83076274e1678">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Kalivendi, S. V. et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem. J. 389, 527–539 (2005)." href="/articles/s41419-021-03614-x#ref-CR84" id="ref-link-section-d83076274e1681">84</a></sup>. FADD and TRADD recruit caspase 8 and activated caspase 8 can activate caspase 3 which results in apoptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Lavrik, I. N. & Krammer, P. H. Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 19, 36–41 (2012)." href="/articles/s41419-021-03614-x#ref-CR85" id="ref-link-section-d83076274e1685">85</a></sup>. Doxorubicin activates the extrinsic apoptotic pathway by activation of nuclear factor-activated T cell-4 (NFAT4) and NF-κB, leading to the upregulation of Fas/FasL and p53; and, downregulation of FLIP, a FLICE/caspase-8 inhibitory protein, which induces Fas-mediated cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Minotti, G., Ronchi, R., Salvatorelli, E., Menna, P. & Cairo, G. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61, 8422–8428 (2001)." href="/articles/s41419-021-03614-x#ref-CR41" id="ref-link-section-d83076274e1689">41</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Kalivendi, S. V. et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem. J. 389, 527–539 (2005)." href="/articles/s41419-021-03614-x#ref-CR84" id="ref-link-section-d83076274e1692">84</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Shati, A. A. Doxorubicin‐induces NFAT/Fas/FasL cardiac apoptosis in rats through activation of calcineurin and P38 MAPK and inhibition of mTOR signalling pathways. Clin. Exp. Pharm. Physiol. 47, 660–676 (2020)." href="/articles/s41419-021-03614-x#ref-CR86" id="ref-link-section-d83076274e1695">86</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Nitobe, J. et al. Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes. Cardiovasc. Res. 57, 119–128 (2003)." href="/articles/s41419-021-03614-x#ref-CR87" id="ref-link-section-d83076274e1698">87</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig5">5</a>).</p><p>Recent evidence suggests that circulating death ligands can act as clinical biomarkers and understanding the extrinsic pathway could have a great therapeutic potential. In a study, investigating the effect of doxorubicin on death ligands in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), death receptors TNFR1, Fas, and death receptor 5 (DR5) were upregulated and DIC was enhanced by physiologically relevant TNF-related apoptosis inducing ligand (TRAIL)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Zhao, L. & Zhang, B. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci. Rep. 7, 44735 (2017)." href="/articles/s41419-021-03614-x#ref-CR88" id="ref-link-section-d83076274e1708">88</a></sup>. This finding suggests that elevated serum levels of specific TNF cytokines due to certain diseases and treatment conditions, could be predictive for the risk of cardiotoxicity prior to the administration of doxorubicin to a patient<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Zhao, L. & Zhang, B. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci. Rep. 7, 44735 (2017)." href="/articles/s41419-021-03614-x#ref-CR88" id="ref-link-section-d83076274e1712">88</a></sup>. Another study using the same model of iPSC-CMs showed that FAS, DR4, and DR5 are the most significantly upregulated genes in RNA-seq data and found that the extrinsic pathway is more upregulated than the intrinsic apoptotic pathway suggesting that blocking the extrinsic pathway could be a more beneficial approach in treating DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="McSweeney, K. M., Bozza, W. P., Alterovitz, W.-L. & Zhang, B. Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity. Cell Death Discov. 5, 102 (2019)." href="/articles/s41419-021-03614-x#ref-CR89" id="ref-link-section-d83076274e1716">89</a></sup>.</p><p>p53 is a key modulator of cell death and has long been implicated with DIC. Doxorubicin upregulates p53 which turns on signaling pathways resulting in extrinsic and intrinsic apoptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Shi, J., Abdelwahid, E. & Wei, L. Apoptosis in anthracycline cardiomyopathy. Curr. Pediatr. Rev. 7, 329–336 (2011)." href="/articles/s41419-021-03614-x#ref-CR72" id="ref-link-section-d83076274e1723">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="McSweeney, K. M., Bozza, W. P., Alterovitz, W.-L. & Zhang, B. Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity. Cell Death Discov. 5, 102 (2019)." href="/articles/s41419-021-03614-x#ref-CR89" id="ref-link-section-d83076274e1726">89</a></sup>. However, recent evidence suggests that p53 involvement in DIC is more complex than originally thought. p53 displays both protective and deleterious effects on the cardiomyocyte depending on the time of doxorubicin treatment and the dose. In the acute setting p53 blockade attenuates apoptotic death, however, chronic p53 deletion augments mitochondrial toxicity and cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Li, J. et al. p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities. Proc. Natl Acad. Sci. USA 116, 19626–19634 (2019)." href="/articles/s41419-021-03614-x#ref-CR90" id="ref-link-section-d83076274e1730">90</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Zhu, W., Zhang, W., Shou, W. & Field, L. J. P53 inhibition exacerbates late-stage anthracycline cardiotoxicity. Cardiovasc. Res. 103, 81–89 (2014)." href="/articles/s41419-021-03614-x#ref-CR91" id="ref-link-section-d83076274e1733">91</a></sup>. p53 has dose-specific effects as well whereby high doxorubicin doses induce p53 dependent apoptosis, while with lower doxorubicin concentrations the mitochondria bioenergetic failure is the main cardiotoxic event<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Cunha-Oliveira, T., Ferreira, L. L., Coelho, A. R., Deus, C. M. & Oliveira, P. J. Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicol. Appl. Pharm. 348, 1–13 (2018)." href="/articles/s41419-021-03614-x#ref-CR92" id="ref-link-section-d83076274e1737">92</a></sup>.</p><p>Another recent finding is the involvement of Wnt signaling in DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hu, Y. et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch. Toxicol. 93, 533–546 (2019)." href="#ref-CR93" id="ref-link-section-d83076274e1745">93</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hu Y. et al. sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. Acta Pharmacol Sin. 41, 1150–1157 (2020)." href="#ref-CR94" id="ref-link-section-d83076274e1745_1">94</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Liang L. et al. Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway. J. Cell Sci. 132, jcs228478 (2019)." href="#ref-CR95" id="ref-link-section-d83076274e1745_2">95</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Xie Z., Xia W., Hou M. Long intergenic non‑coding RNA‑p21 mediates cardiac senescence via the Wnt/β‑catenin signaling pathway in doxorubicin-induced cardiotoxicity. Mol. Med. Rep. 17, 2695–2704 (2017)." href="/articles/s41419-021-03614-x#ref-CR96" id="ref-link-section-d83076274e1748">96</a></sup>. Wnt/β-catenin signaling inhibits apoptosis and has a protective effect in DIC with doxorubicin downregulating this pathway<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Hu, Y. et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch. Toxicol. 93, 533–546 (2019)." href="/articles/s41419-021-03614-x#ref-CR93" id="ref-link-section-d83076274e1752">93</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Liang L. et al. Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway. J. Cell Sci. 132, jcs228478 (2019)." href="/articles/s41419-021-03614-x#ref-CR95" id="ref-link-section-d83076274e1755">95</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Chen, K.-H. et al. Combined therapy with melatonin and exendin-4 effectively attenuated the deterioration of renal function in rat cardiorenal syndrome. Am. J. Transl. Res. 9, 214–229 (2017)." href="/articles/s41419-021-03614-x#ref-CR97" id="ref-link-section-d83076274e1758">97</a></sup>. The Wnt/β-catenin signaling pathway is crucial for many developmental processes including heart development and homeostatic processes, such as apoptosis, cell proliferation, migration, and differentiation<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014)." href="/articles/s41419-021-03614-x#ref-CR98" id="ref-link-section-d83076274e1762">98</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017)." href="/articles/s41419-021-03614-x#ref-CR99" id="ref-link-section-d83076274e1765">99</a></sup>. Deregulation of Wnt/β-catenin is associated with a variety of cardiovascular diseases and impaired cardiogenesis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ozhan, G. & Weidinger, G. Wnt/β-catenin signaling in heart regeneration. Cell Regen. 4, 3 (2015)." href="#ref-CR100" id="ref-link-section-d83076274e1769">100</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Lorenzon, A. et al. Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy. Oncotarget 8, 60640–60655 (2017)." href="#ref-CR101" id="ref-link-section-d83076274e1769_1">101</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Ruiz-Villalba, A. et al. Reference genes for gene expression studies in the mouse heart. Sci. Rep. 7, 1–9 (2017)." href="/articles/s41419-021-03614-x#ref-CR102" id="ref-link-section-d83076274e1772">102</a></sup>.</p><p>A protein involved in the Wnt signaling, the secreted frizzled-related protein 1 (sFRP1), has a location-dependent effect in response to DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Hu, Y. et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch. Toxicol. 93, 533–546 (2019)." href="/articles/s41419-021-03614-x#ref-CR93" id="ref-link-section-d83076274e1779">93</a></sup>. Doxorubicin increases extracellular secretion of sFRP1 and depletes intracellular sFRP1 concentration<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Hu, Y. et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch. Toxicol. 93, 533–546 (2019)." href="/articles/s41419-021-03614-x#ref-CR93" id="ref-link-section-d83076274e1783">93</a></sup>. Clinically, sFRP1 expression is upregulated in samples of DIC hearts compared with healthy hearts, a finding that was replicated in experimental in vivo models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Hu, Y. et al. sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats. Arch. Toxicol. 93, 533–546 (2019)." href="/articles/s41419-021-03614-x#ref-CR93" id="ref-link-section-d83076274e1787">93</a></sup>. Inhibition of sFRP1 secretion attenuated DIC in vitro via the activation of Wnt/β-catenin signaling, while increasing the secretion of sFRP1 had the opposite effect. However, the intracellular concentration of sFRP1 was significantly reduced after doxorubicin exposure both in vitro and in vivo. Knockdown of sFRP1 increased sensitivity to DIC, while overexpression of sFRP1 protected the hearts from DIC. In summary, sFRP1 has a protective intracellular effect but when secreted it damages the heart. As a result, the oversecretion of sFRP1 can be used as a clinical biomarker for DIC. As sFRP1 can regulate both the canonical Wnt/β-catenin and noncanonical Wnt/PCP-JNK pathways the same group also investigated the effect of doxorubicin on Wnt/PCP-JNK signaling<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Matsuyama, M., Aizawa, S. & Shimono, A. Sfrp controls apicobasal polarity and oriented cell division in developing gut epithelium. PLoS Genet. 5, e1000427 (2009)." href="/articles/s41419-021-03614-x#ref-CR103" id="ref-link-section-d83076274e1791">103</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Satoh, W., Matsuyama, M., Takemura, H., Aizawa, S. & Shimono, A. Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/β-catenin and the planar cell polarity pathways during early trunk formation in mouse. Genesis 46, 92–103 (2008)." href="/articles/s41419-021-03614-x#ref-CR104" id="ref-link-section-d83076274e1794">104</a></sup>. Although, doxorubicin downregulates Wnt/β-catenin signaling, in the case of Wnt/PCP-JNK signaling it upregulates it<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Hu Y. et al. sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. Acta Pharmacol Sin. 41, 1150–1157 (2020)." href="/articles/s41419-021-03614-x#ref-CR94" id="ref-link-section-d83076274e1798">94</a></sup>. Pretreatment with a Wnt/PCP-JNK signaling inhibitor, reduced doxorubicin-induced apoptosis in vitro, while sFRP1 overexpression protected from DIC through the downregulation of Wnt/PCP-JNK signaling<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Hu Y. et al. sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. Acta Pharmacol Sin. 41, 1150–1157 (2020)." href="/articles/s41419-021-03614-x#ref-CR94" id="ref-link-section-d83076274e1803">94</a></sup>. Finally, another group reported that Dickkopf-1 (Dkk1) gets activated during doxorubicin treatment and inhibits the canonical Wnt/β-catenin pathway leading to increased cardiomyocyte apoptosis and mitochondria dysfunction<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Liang L. et al. Dkk1 exacerbates doxorubicin-induced cardiotoxicity by inhibiting the Wnt/β-catenin signaling pathway. J. Cell Sci. 132, jcs228478 (2019)." href="/articles/s41419-021-03614-x#ref-CR95" id="ref-link-section-d83076274e1807">95</a></sup>. Blockade of Dkk1 attenuated DIC, while overexpression of Dkk1 had the opposite effect. In summary, activating the Wnt/β-catenin signaling pathway during doxorubicin treatment can protect from DIC according to in vivo and in vitro models, and pharmacological agents blocking inhibitors of this pathway such as Dkk1 or activating inducers such as intracellular sFRP1 can protect from DIC.</p><h3 class="c-article__sub-heading" id="Sec10">Sirtuins in DIC</h3><p>In the heart, sirtuins (SIRT) 1, 2, 3, and 6 activate the autophagic process, repress apoptosis and protect the heart from various cardiovascular threats such as atherosclerosis, ischemia-reperfusion injury, myocardial hypertrophy, diabetic cardiomyopathy, and cardiac hypertrophy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Lee, I. H. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp. Mol. Med. 51, 1–11 (2019)." href="/articles/s41419-021-03614-x#ref-CR105" id="ref-link-section-d83076274e1818">105</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Matsushima, S. & Sadoshima, J. The role of sirtuins in cardiac disease. Am. J. Physiol. Circ. Physiol. 309, H1375–H1389 (2015)." href="/articles/s41419-021-03614-x#ref-CR106" id="ref-link-section-d83076274e1821">106</a></sup>.</p><p>Sirtuins may play a protective role in DIC (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig6">6</a>). In rodents, doxorubicin treatment downregulates Sirt1 expression, increases ROS production and cell death. Overexpression of Sirt1 or resveratrol treatment, a SIRT1 agonist, and an autophagy activator, reverses the DIC phenotype<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Ruan, Y. et al. SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell Physiol. Biochem. 35, 1116–1124 (2015)." href="/articles/s41419-021-03614-x#ref-CR107" id="ref-link-section-d83076274e1831">107</a></sup>. Similarly, doxorubicin reduces Sirt1 expression in the myocardium, leading to excess cellular damage, mitochondrial dysfunction, oxidative stress, and apoptosis. Berberine, an alkaloid herbal extract, and agonist of Sirt1 reduces DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Wu, Y.-Z., Zhang, L., Wu, Z.-X., Shan, T. & Xiong, C. Berberine ameliorates doxorubicin-induced cardiotoxicity via a SIRT1/p66Shc-mediated pathway. Oxid. Med. Cell Longev. 2019, 1–14 (2019)." href="/articles/s41419-021-03614-x#ref-CR27" id="ref-link-section-d83076274e1835">27</a></sup>. The effect of Sirt1 on DIC appears to be dependent on fibroblast growth factor 21 (FGF21), as inhibition of Sirt1 attenuates the protective effects of FGF21 against DIC in mice<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Wang, S., Wang, Y., Zhang, Z., Liu, Q. & Gu, J. Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway. Cell Death Dis. 8, e3018–e3018 (2017)." href="/articles/s41419-021-03614-x#ref-CR108" id="ref-link-section-d83076274e1839">108</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Role of Sirtuins in doxorubicin-induced cardiotoxicity."><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 6: Role of Sirtuins in doxorubicin-induced cardiotoxicity.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig6_HTML.png?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig6_HTML.png" alt="figure 6" loading="lazy" width="685" height="557"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p>Doxorubicin downregulates SIRT1, causing increased oxidative damage, loss of mitochondria integrity, AMPK, and NLRP activation resulting in increased apoptosis, autophagy, and pyroptosis. Berberine, FGF21, and resveratrol protect from DIC via SIRT1 activation. Doxorubicin downregulates SIRT2 via miRNA-140-5p, leading to reduced SIRT2 and NRF2 expression. SIRT2 has been implicated with iron homeostasis while NRF2 activation is involved in doxorubicin-induced ferroptosis. Doxorubicin-induced downregulation of SIRT3 causes increased oxidative damage and loss of mitochondria integrity leading to increased apoptosis. Berberine and honokiol protect from DIC via SIRT3 upregulation. Doxorubicin treatment reduces the expression of SIRT6 leading to repression of GATA4 and increased apoptosis. SIRT Sirtuin, DOX doxorubicin, FGF21 fibroblast growth factor 21, Nrf2 nuclear factor erythroid 2-related factor 2, GATA4 GATA-binding protein 4.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>SIRT3, a mitochondrial sirtuin protects the heart against myocardial hypertrophy, diabetic cardiomyopathy, and DIC. Doxorubicin treatment reduces Sirt3 expression in vivo and in vitro in rodent hearts<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Coelho, A. R. et al. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim. Biophys. Acta 1863, 2904–2923 (2017)." href="/articles/s41419-021-03614-x#ref-CR26" id="ref-link-section-d83076274e1865">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Pillai, V. B. et al. Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. Am. J. Physiol. Circ. Physiol. 310, H962–H972 (2016)." href="/articles/s41419-021-03614-x#ref-CR109" id="ref-link-section-d83076274e1868">109</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Pillai V. B. et al. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 8, 34082–34098 (2017)." href="/articles/s41419-021-03614-x#ref-CR110" id="ref-link-section-d83076274e1871">110</a></sup>. In the same manner, overexpression of Sirt3 protects the heart from doxorubicin by reducing oxidative damage and maintains mitochondrial integrity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Coelho, A. R. et al. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim. Biophys. Acta 1863, 2904–2923 (2017)." href="/articles/s41419-021-03614-x#ref-CR26" id="ref-link-section-d83076274e1875">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Pillai, V. B. et al. Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. Am. J. Physiol. Circ. Physiol. 310, H962–H972 (2016)." href="/articles/s41419-021-03614-x#ref-CR109" id="ref-link-section-d83076274e1878">109</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Samant, S. A. et al. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol. Cell Biol. 34, 807–819 (2014)." href="/articles/s41419-021-03614-x#ref-CR111" id="ref-link-section-d83076274e1881">111</a></sup>. Sirt3 activators, honokiol, and berberine improve cellular damage in the heart induced by doxorubicin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Coelho, A. R. et al. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim. Biophys. Acta 1863, 2904–2923 (2017)." href="/articles/s41419-021-03614-x#ref-CR26" id="ref-link-section-d83076274e1885">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Pillai V. B. et al. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 8, 34082–34098 (2017)." href="/articles/s41419-021-03614-x#ref-CR110" id="ref-link-section-d83076274e1888">110</a></sup>. Consistent with this, <i>Sirt3</i> knockout mice died before completing doxorubicin treatment<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Pillai, V. B. et al. Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. Am. J. Physiol. Circ. Physiol. 310, H962–H972 (2016)." href="/articles/s41419-021-03614-x#ref-CR109" id="ref-link-section-d83076274e1895">109</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig6">6</a>).</p><p>SIRT6 is located predominately in the nucleus and similarly to SIRT3 protects the heart from cardiac hypertrophy and DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Lee, I. H. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp. Mol. Med. 51, 1–11 (2019)." href="/articles/s41419-021-03614-x#ref-CR105" id="ref-link-section-d83076274e1906">105</a></sup>. Doxorubicin treatment reduces the expression of SIRT6 leading to repression of GATA4 an antiapoptotic gene<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Peng, L. et al. Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis. Nucleic Acids Res 48, 4992–5005 (2020)." href="/articles/s41419-021-03614-x#ref-CR112" id="ref-link-section-d83076274e1910">112</a></sup>. Under normal conditions, SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4, and then GATA4 suppresses SIRT6’s deacetylase activity. Doxorubicin can block the assembly of the SIRT6–TIP60–GATA4 trimeric complex and decrease the expression of GATA4 which results in cell death. In addition, GATA4 hyperacetylation-mimic protects against DIC providing evidence that the Sirt6–TIP60–GATA4 trimeric complex could be a new therapeutic target against DIC<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Peng, L. et al. Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis. Nucleic Acids Res 48, 4992–5005 (2020)." href="/articles/s41419-021-03614-x#ref-CR112" id="ref-link-section-d83076274e1914">112</a></sup>. Finally, a recent study showed that pregnant mice who exercised during doxorubicin treatment managed to increase their Sirt6 expression and improve viability in progeny’s hearts compared to the control group that did not exercise<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 113" title="Brito, V. B. et al. Exercise during pregnancy decreases doxorubicin-induced cardiotoxic effects on neonatal hearts. Toxicology 368–369, 46–57 (2016)." href="/articles/s41419-021-03614-x#ref-CR113" id="ref-link-section-d83076274e1918">113</a></sup> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig6">6</a>).</p><p>The role of SIRT4, 5, and 7 in DIC has yet to be studied. One study has investigated the effect of SIRT2 on DIC and showed that doxorubicin treatment increases expression of the miRNA 140-5p, which in turn suppresses the expression of Nrf2 and Sirt2 leading to increased cell death<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Zhao, L. et al. MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biol. 15, 284–296 (2018)." href="/articles/s41419-021-03614-x#ref-CR114" id="ref-link-section-d83076274e1929">114</a></sup>.</p><p>In summary, in vivo, and in vitro models provide mounting evidence that activating sirtuins with agents such as berberine and resveratrol reduces the severity of DIC and may serve as potential therapeutic approaches.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec11-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec11">Discussion</h2><div class="c-article-section__content" id="Sec11-content"><p>As the number of cancer survivors is growing, chemotherapy-related cardiotoxicity represents an increasing health problem for the future. Doxorubicin causes cardiotoxicity through multiple mechanisms including autophagy, apoptosis, necroptosis, ferroptosis, pyroptosis, and others. Understanding these mechanisms is essential in order to identify pharmacological agents that block these pathways and also understand the functional impact of genetic variants that have been associated with DIC.</p><p>Substantial effort has been put in utilizing agents that decrease ROS production, however, they have failed to reduce cardiotoxicity, indicating that the mechanism of DIC involves more than just oxidative stress as was initially suggested<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Gianni, L. et al. Anthracycline cardiotoxicity: From bench to bedside. J. Clin. Oncol. 26, 3777–3784 (2008)." href="/articles/s41419-021-03614-x#ref-CR115" id="ref-link-section-d83076274e1948">115</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Takemura, G. & Fujiwara, H. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog. Cardiovasc. Dis. 49, 330–352 (2007)." href="/articles/s41419-021-03614-x#ref-CR116" id="ref-link-section-d83076274e1951">116</a></sup>. With a clearer understanding of the predominant cell death pathways by which doxorubicin kills the cell, new agents that target these pathways can be trialed. For example, triggering autophagy prior to doxorubicin treatment using pharmacological agents or caloric restriction has promising results in attenuating DIC in rodent models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hall, S. E., Smuder, A. J. & Hayward, R. Effects of calorie restriction and voluntary exercise on doxorubicin-induced cardiotoxicity. Integr. Cancer Ther. 18, 153473541984399 (2019)." href="#ref-CR34" id="ref-link-section-d83076274e1955">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dutta, D., Xu, J., Dirain, M. L. S. & Leeuwenburgh, C. Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity. Free Radic. Biol. Med. 74, 252–262 (2014)." href="#ref-CR35" id="ref-link-section-d83076274e1955_1">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mitra, M. S., Donthamsetty, S., White, B., Latendresse, J. R. & Mehendale, H. M. Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. Toxicol. Appl. Pharm. 225, 90–101 (2007)." href="#ref-CR36" id="ref-link-section-d83076274e1955_2">36</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kawaguchi, T. et al. Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res. 96, 456–465 (2012)." href="#ref-CR37" id="ref-link-section-d83076274e1955_3">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Xu, X. et al. Macrophage migration inhibitory factor (MIF) deficiency exacerbates aging-induced cardiac remodeling and dysfunction despite improved inflammation: role of autophagy regulation. Sci. Rep. 6, 22488 (2016)." href="/articles/s41419-021-03614-x#ref-CR38" id="ref-link-section-d83076274e1958">38</a></sup>. Similarly, blockade of ferroptosis shows encouraging outcomes in pre-clinical models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019)." href="/articles/s41419-021-03614-x#ref-CR52" id="ref-link-section-d83076274e1962">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e1965">54</a></sup>. However, these novel findings are yet to be assessed in clinical trials.</p><p>Many cardioprotectants discovered that protect from DIC in experimental models fail to reach clinical trials. One reason is that there are controversies and discrepancies in the RCD pathways involved in DIC. For example, it remains unclear whether autophagy plays a primarily protective or disruptive effect during doxorubicin treatment. Given the complexity of doxorubicin’s cellular effects, understanding the precise cell death pathways involved remains a significant challenge.</p><p>One promising opportunity for future study is the effect of genetic variants associated with DIC that may offer mechanistic insights into cell death pathways involved in DIC. For example, a genetic-wide association study identified a genetic variant in the retinoic acid receptor gamma (RARG-S427L) that increases susceptibility to doxorubicin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Aminkeng, F. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 47, 1079–1084 (2015)." href="/articles/s41419-021-03614-x#ref-CR117" id="ref-link-section-d83076274e1975">117</a></sup>. Recently, the functional impact of this variant was validated in an iPSC-CMs model<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Christidi, E. et al. Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes. Sci. Rep. 10, 10363 (2020)." href="/articles/s41419-021-03614-x#ref-CR118" id="ref-link-section-d83076274e1979">118</a></sup>. Doxorubicin-treated iPSC-CMs harboring this mutation experienced increased cell death, ROS production, and double-strand breaks<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Christidi, E. et al. Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes. Sci. Rep. 10, 10363 (2020)." href="/articles/s41419-021-03614-x#ref-CR118" id="ref-link-section-d83076274e1983">118</a></sup>. The precise mechanism by which variation in the RARG causes cell death is yet to be elucidated. Two possible mechanisms could explain how this genetic variation affects doxorubicin-induced cardiomyocyte death (i) RARG-S427L upregulates TOP2B leading to double-strand breaks<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Aminkeng, F. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 47, 1079–1084 (2015)." href="/articles/s41419-021-03614-x#ref-CR117" id="ref-link-section-d83076274e1987">117</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Christidi, E. et al. Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes. Sci. Rep. 10, 10363 (2020)." href="/articles/s41419-021-03614-x#ref-CR118" id="ref-link-section-d83076274e1990">118</a></sup>, (ii) RARG-S427L could make cells more susceptible to doxorubicin via necroptosis; as it has been shown that RARG can complex to RIPK1 to induce necroptosis in mouse embryonic fibroblasts in response to chemotherapy drugs including doxorubicin<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Kadigamuwa, C. et al. Role of retinoic acid receptor-γ in DNA damage-induced necroptosis. iScience 17, 74–86 (2019)." href="/articles/s41419-021-03614-x#ref-CR119" id="ref-link-section-d83076274e1994">119</a></sup>. Verifying genetic variants that are associated with DIC and understanding their mechanisms not only will it allow to identify their impact on cell signaling pathways but it will also have a tremendous therapeutic potential allowing genetic testing prior to the administration of the drug.</p><p>In addition, deepening our understanding of the RCD pathways involved in cardiomyocyte cell death may improve the evaluation of drug-induced cardiotoxicity. Many studies evaluate cardiotoxicity based primarily on the apoptotic pathway. However, other RCD pathways may have a significant contribution to drug-related cardiomyocyte toxicity and therefore a more comprehensive experimental approach may better predict clinical cardiotoxicity.</p><p>Multiple RCD pathways are involved in doxorubicin’s effects on cardiomyocytes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig7">7</a>). These multi-factorial mechanisms can occur simultaneously, are not independent, and may overlap or crosstalk, adding to the complexity of DIC. Sirtuins for example are involved in autophagy, apoptosis, and pyroptosis (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig6">6</a>), while also they have been associated with cell death due to iron overload as well<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Yang, X. et al. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J. Clin. Investig. 127, 1505–1516 (2017)." href="/articles/s41419-021-03614-x#ref-CR120" id="ref-link-section-d83076274e2011">120</a></sup>. Similarly, CAMKII activation leading to mPTP opening can occur in both necroptosis and apoptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016)." href="/articles/s41419-021-03614-x#ref-CR59" id="ref-link-section-d83076274e2015">59</a></sup>. However, the involvement of identical molecules in multiple pathways may represent an opportunity as the same pharmacological agent can potentially block multiple pathways simultaneously. Berberine can activate SIRT1 which in turn can regulate autophagy, apoptosis, and pyroptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Lv, X. et al. Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS ONE 7, e47351 (2012)." href="/articles/s41419-021-03614-x#ref-CR19" id="ref-link-section-d83076274e2019">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Coelho, A. R. et al. Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts. Biochim. Biophys. Acta 1863, 2904–2923 (2017)." href="/articles/s41419-021-03614-x#ref-CR26" id="ref-link-section-d83076274e2022">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Wu, Y.-Z., Zhang, L., Wu, Z.-X., Shan, T. & Xiong, C. Berberine ameliorates doxorubicin-induced cardiotoxicity via a SIRT1/p66Shc-mediated pathway. Oxid. Med. Cell Longev. 2019, 1–14 (2019)." href="/articles/s41419-021-03614-x#ref-CR27" id="ref-link-section-d83076274e2025">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Sun, Z. et al. Dihydromyricetin alleviates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome through activation of SIRT1. Biochem. Pharm. 175, 113888 (2020)." href="/articles/s41419-021-03614-x#ref-CR70" id="ref-link-section-d83076274e2028">70</a></sup>. While dexrazoxane was thought to only exert its cardioprotective effects through iron chelation, it has now been established that it works by blocking TOP2B as well<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Deng S. et al. Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms. BMC Cancer 14, 842 (2014)." href="/articles/s41419-021-03614-x#ref-CR121" id="ref-link-section-d83076274e2033">121</a></sup>. As a result, understanding the crosstalk between RCD pathways will allow for the identification of therapeutic agents that target multiple pathways at once.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-7" data-title="Doxorubicin-induced regulated cell death pathways."><figure><figcaption><b id="Fig7" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 7: Doxorubicin-induced regulated cell death pathways.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/7" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig7_HTML.png?as=webp"><img aria-describedby="Fig7" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41419-021-03614-x/MediaObjects/41419_2021_3614_Fig7_HTML.png" alt="figure 7" loading="lazy" width="685" height="370"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-7-desc"><p>Summary of regulated cell death pathways triggered by doxorubicin in the heart. Doxorubicin triggers ROS production by inducing initiation of autophagy and by blocking lysosomal proteolysis resulting in the accumulation of autophagosomes and autolysosomes. Doxorubicin undergoes both redox cycling forming dox-semiquinone moieties and Fenton reaction creating oxidative species. Excess iron and lipid peroxidation due to doxorubicin treatment results in ferroptosis. Doxorubicin activates NLRP inducing the release of Il-1β and Il-18 resulting in death due to pyroptosis. RIPK1 and RIPK3 activation due to doxorubicin treatment leads to phosphorylation of MLKL and necroptosis. Doxorubicin causes necroptosis through RIPK1 independent pathway by activating RIPK3 and CAMKII leading to mPTP and membrane potential loss. ROS trigger p53 activation and GATA4 downregulation stimulating the intrinsic apoptotic pathway. Doxorubicin treatment upregulates death receptors and together with the activation of NFAT and NF-κΒ the extrinsic apoptotic pathway is triggered. Pink color capsules represent apoptosis, brown color capsules represent necroptosis, blue color capsules represent ferroptosis and white capsules represent pyroptosis. DOX doxorubicin, ROS reactive oxygen species, Tf transferrin, TfR transferrin receptor, GPX4 glutathione peroxidase 4, mPTP mitochondria permeability transition pore, Lipid-OO lipid peroxides, NLRP3 NOD−, LRR−, and pyrin domain-containing protein 3, TINCR terminal differentiation-induced ncRNA, GSDM-N gasdermin, TNFα tumor necrosis factor-alpha, TRADD tumor necrosis factor receptor type 1 associated death domain protein, FADD Fas-associated protein with death domain, RIPK receptor-interacting serine/threonine-protein kinase, CAMKII calcium/calmodulin-dependent protein kinase II, NRF2 nuclear factor erythroid 2-related factor, TFEB Transcription factor EB, NF-κΒ nuclear factor-κB, NFAT4 nuclear factor of activated T-cells, ROS reactive oxygen species, SIRT sirtuin, GATA4 GATA-binding protein 4.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41419-021-03614-x/figures/7" data-track-dest="link:Figure7 Full size image" aria-label="Full size image figure 7" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Understanding which RCD has the greatest effect in DIC would help prioritize which pathway to be preferentially blocked. Necrosis and necroptosis may have a greater responsibility in the pathogenesis of DIC compared to apoptosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Zhang, T. et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis. Nat. Med. 22, 175–182 (2016)." href="/articles/s41419-021-03614-x#ref-CR59" id="ref-link-section-d83076274e2059">59</a></sup>. However, ferroptosis and apoptosis also play important roles as well<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tadokoro T. et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 5, e132747 (2020)." href="/articles/s41419-021-03614-x#ref-CR54" id="ref-link-section-d83076274e2063">54</a></sup>. Evidently, identifying which pathways have the greatest responsibility in the pathogenesis of DIC requires further study.</p><p>Novel RCD pathways are continuously emerging and new key players within RCD pathways are also being discovered. Studying RCD pathways involved in DIC has led to significant advances in our understanding of the complex molecular pathogenesis of this important adverse drug reaction, and it is likely that there will be many future advances in this field. 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Figure 1 was adapted from “Autophagy Process”, also included in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig7">7</a>. Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41419-021-03614-x#Fig5">5</a> was adapted from “Intrinsic and Extrinsic Apoptosis” by BioRender.com (2020). <a href="https://app.biorender.com/biorender-templates">https://app.biorender.com/biorender-templates</a>.</p></div></div></section><section data-title="Funding"><div class="c-article-section" id="Fun-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Fun">Funding</h2><div class="c-article-section__content" id="Fun-content"><p>This work was supported by a Project grant from the Canadian Institutes of Health Research (PJT153118 to L.R.B.). L.R.B. is a Michael Smith Foundation for Health Research Scholar and a Canada Research Chair in Precision Cardiovascular Disease Prevention.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, BC, Canada</p><p class="c-article-author-affiliation__authors-list">Effimia Christidi & Liam R. Brunham</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Medicine, University of British Columbia, Vancouver, BC, Canada</p><p class="c-article-author-affiliation__authors-list">Liam R. Brunham</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada</p><p class="c-article-author-affiliation__authors-list">Liam R. 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L.R.B. wrote and reviewed this work.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:liam.brunham@ubc.ca">Liam R. 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Christidi, E., Brunham, L.R. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. <i>Cell Death Dis</i> <b>12</b>, 339 (2021). https://doi.org/10.1038/s41419-021-03614-x</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41419-021-03614-x?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2020-12-03">03 December 2020</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Revised<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2021-03-10">10 March 2021</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2021-03-11">11 March 2021</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2021-04-01">01 April 2021</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.1038/s41419-021-03614-x</span></p></li></ul><div data-component="share-box"><div 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