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class='row panel-padding'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row cover-caption'> <div class='small-12 columns'> <h3 class='issue'> Issue published April 1, 2025 <span class='browse'> <a id="issue#show_previous_issue" href="/135/6">Previous issue</a> </span> </h3> </div> </div> <div class='row'> <div class='large-3 medium-4 columns'> <img class="issue-cover" src="//dm5migu4zj3pb.cloudfront.net/volumes/135/7/135-7-cover.jpg" /> </div> <div class='large-9 medium-8 columns'> <ul class='no-bullet'> <li> Volume 135, Issue 7 </li> </ul> <h5>Go to section:</h5> <ul class='no-bullet'> <li> <a href='#conversations_with_giants_in_medicine'> Conversations with Giants in Medicine </a> </li> <li> <a href='#review_series_viewpoint'> Review Series Viewpoint </a> </li> <li> <a href='#review_series'> Review Series </a> </li> <li> <a href='#editor_s_note'> Editor's note </a> </li> <li> <a href='#commentary'> Commentaries </a> </li> <li> <a href='#research_article'> Research Articles </a> </li> </ul> </div> </div> <div class='row'> <div class='small-12 columns'> <h4 class='cover-story-headline'> On the cover: Protein aggregation in the post–myocardial infarction myocardium </h4> <div><p><a href="/articles/view/167730">Islam, Rawnsley, and colleagues</a> report that phosphorylation of CRYAB, a cardiac myocyte–enriched chaperone protein, after myocardial infarction promotes protein aggregates and contributes to heart failure. The cover image depicts abnormal condensates driven by phosphorylated CRYAB (blue on red) molecules that trap desmin (yellow) to form aggregates. This prevents the physiologic localization of desmin as a scaffold holding linear arrays of sarcomeres (pink) together, causing sarcomere disarray and cardiomyopathy. Image credit: Anthony Bartley.</p> </div> </div> </div> <a class='in-page' name='conversations_with_giants_in_medicine'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel0' name='conversations_with_giants_in_medicine'> <strong></strong> <span class='toggle-icon'></span> Conversations with Giants in Medicine </a> <div class='content active' id='panel0'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/193004">Ending one conversation, starting another</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/193004">Ushma S. Neill</a> <a class='hide-for-small show-more' data-reveal-id='article45903-more' href='#'> <div class='article-authors'> Ushma S. Neill </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e193004. <a href="https://doi.org/10.1172/JCI193004">https://doi.org/10.1172/JCI193004</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/193004">Text</a> | <a href="/articles/view/193004/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI193004' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/193004/figure/1' ref='group' title='Ushma Neill, Semyon Maltsev, and Alexey Levchenko in NYC, September 2023.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/193000/193004/small/JCI193004.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45903-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/193004">Ending one conversation, starting another</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/193004">Text</a></li> <li><a class="button tiny" href="/articles/view/193004/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ushma S. Neill</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='review_series_viewpoint'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel1' name='review_series_viewpoint'> <strong></strong> <span class='toggle-icon'></span> Review Series Viewpoint </a> <div class='content active' id='panel1'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186418">Fat, fibrosis, and the future: navigating the maze of MASLD/MASH</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186418">Scott L. Friedman</a> <a class='hide-for-small show-more' data-reveal-id='article45919-more' href='#'> <div class='article-authors'> Scott L. Friedman </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e186418. <a href="https://doi.org/10.1172/JCI186418">https://doi.org/10.1172/JCI186418</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186418">Text</a> | <a href="/articles/view/186418/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186418' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186418/figure/1' ref='group' title='Concerns about the increasing worldwide prevalence, economic impact, and serious adverse sequelae of MASLD and MASH draw attention to its pathogenesis and treatment options.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186418/small/JCI186418.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45919-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186418">Fat, fibrosis, and the future: navigating the maze of MASLD/MASH</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186418">Text</a></li> <li><a class="button tiny" href="/articles/view/186418/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Scott L. Friedman</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='review_series'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel2' name='review_series'> <strong></strong> <span class='toggle-icon'></span> Review Series </a> <div class='content active' id='panel2'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186423">Metabolic dysfunction–associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186423">Bernd Schnabl, … , Christopher J. Damman, Rotonya M. Carr</a> <a class='hide-for-small show-more' data-reveal-id='article45914-more' href='#'> <div class='article-authors'> Bernd Schnabl, … , Christopher J. Damman, Rotonya M. Carr </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e186423. <a href="https://doi.org/10.1172/JCI186423">https://doi.org/10.1172/JCI186423</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186423">Text</a> | <a href="/articles/view/186423/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186423' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186423/figure/1' ref='group' title='Gut barrier dysfunction in MASLD. The intestinal epithelial barrier provides the main line of defense against translocation of gut microbiota. The barrier includes epithelial cell microvilli, an outer and inner mucous layer, and tight junction proteins located between adjacent epithelial cells. The figure compares (A) a normal intestinal epithelial barrier with diverse gut microbiome to (B) an impaired intestinal epithelial barrier as observed in MASLD with subsequent translocation of bacterial products, metabolites, and viable bacteria.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186423/small/JCI186423.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45914-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186423">Metabolic dysfunction–associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186423">Text</a></li> <li><a class="button tiny" href="/articles/view/186423/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic dysfunction–associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Bernd Schnabl, Christopher J. Damman, Rotonya M. Carr</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186424">Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186424">Vincent L. Chen, … , Nicholette D. Palmer, Elizabeth K. Speliotes</a> <a class='hide-for-small show-more' data-reveal-id='article45898-more' href='#'> <div class='article-authors'> Vincent L. Chen, … , Nicholette D. Palmer, Elizabeth K. Speliotes </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e186424. <a href="https://doi.org/10.1172/JCI186424">https://doi.org/10.1172/JCI186424</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186424">Text</a> | <a href="/articles/view/186424/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186424' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186424/figure/1' ref='group' title='PRSs. (A) Sample distribution of risk alleles, which when combined and weighted by effect size, can contribute to calculation of a continuous PRS. (B) Sample PRS plotted versus the percentage of individuals with cirrhosis to show how this score can identify some individuals with high risk of developing the disease.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186424/small/JCI186424.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45898-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186424">Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186424">Text</a></li> <li><a class="button tiny" href="/articles/view/186424/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic dysfunction–associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Vincent L. Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B. Patel, Nicholette D. Palmer, Elizabeth K. Speliotes</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='editor_s_note'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel3' name='editor_s_note'> <strong></strong> <span class='toggle-icon'></span> Editor's note </a> <div class='content active' id='panel3'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/193039">Unveiling the cholesterol-hemangioma axis: a path to new treatments</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/193039">M. Luisa Iruela-Arispe</a> <a class='hide-for-small show-more' data-reveal-id='article45911-more' href='#'> <div class='article-authors'> M. Luisa Iruela-Arispe </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e193039. <a href="https://doi.org/10.1172/JCI193039">https://doi.org/10.1172/JCI193039</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/193039">Text</a> | <a href="/articles/view/193039/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI193039' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45911-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/193039">Unveiling the cholesterol-hemangioma axis: a path to new treatments</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/193039">Text</a></li> <li><a class="button tiny" href="/articles/view/193039/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>M. Luisa Iruela-Arispe</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='commentary'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel4' name='commentary'> <strong></strong> <span class='toggle-icon'></span> Commentaries </a> <div class='content active' id='panel4'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190471">Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190471">Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska</a> <a class='hide-for-small show-more' data-reveal-id='article45891-more' href='#'> <div class='article-authors'> Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e190471. <a href="https://doi.org/10.1172/JCI190471">https://doi.org/10.1172/JCI190471</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190471">Text</a> | <a href="/articles/view/190471/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190471' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190471/figure/1' ref='group' title='TRAF3 has a regulatory role in GBM via PUFA metabolism and its hypermethylation. (A) In the context of GBM, promoter hypermethylation suppresses TRAF3 expression. The absence of TRAF3 permits ECH1-mediated metabolism of PUFAs and efficient FAO. (B) Zeng et al. showed that TRAF3 overexpression resulted in the ubiquitination (Ub) of ECH1, which impeded FAO, promoted lipid peroxidation, and induced ferroptosis. Furthermore, ECH1 depletion via shRNA induced mitochondrial damage and inhibited tumorigenesis. These findings underscore the therapeutic potential of targeting hypermethylation and the TRAF3/ECH1 axis to suppress tumor growth and enhance sensitivity to immunotherapy.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190471/small/JCI190471.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45891-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190471">Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190471">Text</a></li> <li><a class="button tiny" href="/articles/view/190471/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Glioblastoma (GBM), the most aggressive type of primary brain tumor, continues to defy therapeutic advances with its metabolic adaptability and resistance to treatment. In this issue of the JCI, Zeng et al. delve into a pivotal mechanism underpinning this adaptability. They identified an important role for TNF receptor–associated factor 3 (TRAF3) in regulating lipid metabolism through its interaction with enoyl-CoA hydratase 1 (ECH1). These findings elucidate a unique signaling axis that shields GBM cells from lipid peroxidation and antitumor immunity, advancing therapeutic strategies for GBM that may also carry over to other cancers with similar metabolic vulnerabilities.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tzu-Yi Chia, Nishanth S. Sadagopan, Jason Miska</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191094">ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191094">Sophie O’Keefe, Qiwei Wang</a> <a class='hide-for-small show-more' data-reveal-id='article45912-more' href='#'> <div class='article-authors'> Sophie O’Keefe, Qiwei Wang </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191094. <a href="https://doi.org/10.1172/JCI191094">https://doi.org/10.1172/JCI191094</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191094">Text</a> | <a href="/articles/view/191094/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191094' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191094/figure/1' ref='group' title='Acetyl-CoA acetyltransferase 1 functions as a metabolic regulator of tertiary lymphoid structures in non–small cell lung cancer. Tumor cell–intrinsic Acetyl-CoA acetyltransferase 1 (ACAT1) interacts with succinyl-CoA, driving hypersuccinylation at lysines (Ksucc) of mitochondrial proteins, which enhances intratumoral reactive oxygen species (ROS). This oxidative stress suppresses B cells, thereby inhibiting the formation of tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). NSCLC, non–small cell lung cancer; DC, dendritic cell.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191094/small/JCI191094.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45912-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191094">ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191094">Text</a></li> <li><a class="button tiny" href="/articles/view/191094/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Non–small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sophie O’Keefe, Qiwei Wang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191355"><i>HoxBlinc</i>: a key driver of chromatin dynamics in NUP98 fusion–driven leukemia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191355">Jian Xu, Wei Du</a> <a class='hide-for-small show-more' data-reveal-id='article45915-more' href='#'> <div class='article-authors'> Jian Xu, Wei Du </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191355. <a href="https://doi.org/10.1172/JCI191355">https://doi.org/10.1172/JCI191355</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191355">Text</a> | <a href="/articles/view/191355/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191355' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191355/figure/1' ref='group' title='HoxBlinc modulates oncogenic transcription and leukemogenesis in NUP98 fusion–driven leukemia. (A) NUP98 fusion induces aberrant activation of HoxBlinc, causing a reorganization of TADs that alters chromatin interactions. HoxBlinc facilitates chromatin accessibility of MLL1 at promoter regions, ultimately enhancing the expression of HOX and other oncogenic genes. (B) Loss of HoxBlinc reduces MLL1 recruitment and decreases leukemic gene transcription.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191355/small/JCI191355.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45915-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191355"><i>HoxBlinc</i>: a key driver of chromatin dynamics in NUP98 fusion–driven leukemia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191355">Text</a></li> <li><a class="button tiny" href="/articles/view/191355/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Nucleoporin 98 (NUP98) fusion oncogenes are known to promote aggressive pediatric leukemia by disrupting chromatin structure and modulating the expression of homeobox (HOX) genes, yet the precise molecular events are unclear. In this issue of the JCI, K. Hamamoto et al. explore the mechanistic underpinnings of NUP98 fusion–driven pediatric leukemia, with a focus on aberrant activation of the Hoxb-associated long, noncoding RNA (lncRNA) HoxBlinc. The authors provide compelling evidence that HoxBlinc plays a central role in the oncogenic transformation associated with NUP98 fusion protein. The study underscores a CTCF-independent role of HoxBlinc in the regulation of topologically associated domains (TADs) and chromatin accessibility, which has not been fully appreciated in previous research on the NUP98 fusion oncogenes. The discovery of HoxBlinc lncRNA as a downstream regulator of NUP98 fusion oncoproteins offers a potential target for therapeutic intervention in pediatric leukemia.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jian Xu, Wei Du</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191422">Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191422">Qun Chen, … , Michael S. Bronze, Min Li</a> <a class='hide-for-small show-more' data-reveal-id='article45902-more' href='#'> <div class='article-authors'> Qun Chen, … , Michael S. Bronze, Min Li </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191422. <a href="https://doi.org/10.1172/JCI191422">https://doi.org/10.1172/JCI191422</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191422">Text</a> | <a href="/articles/view/191422/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191422' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191422/figure/1' ref='group' title='Lactate-induced ENSA-K63 lactylation drives the formation of an immunosuppressive microenvironment in PDAC. In PDAC cells, lactate, generated by LDH during glycolysis, induces ENSA-K63 lactylation (la), which inhibits PP2A activity and sustains SRC phosphorylation. This activation triggers STAT3 phosphorylation, driving the transcriptional upregulation of CCL2. CCL2 recruits macrophages via CCR2. Separately, extracellular lactate secreted by tumor cells through MCTs is taken up by macrophages, further reprogramming them through the ENSA/SRC/STAT3/CCL2 axis and amplifying the expression of genes encoding immunosuppressive factors (including CCL2, ARG1, S100A9, and IL10). These processes establish an immunosuppressive microenvironment and promote resistance to T cell–mediated antitumor immunity and PD-1–mediated immunotherapy.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191422/small/JCI191422.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45902-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191422">Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191422">Text</a></li> <li><a class="button tiny" href="/articles/view/191422/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Qun Chen, Hao Yuan, Michael S. Bronze, Min Li</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191423">Insights into protection against <i>Mycobacterium tuberculosis</i> infection: time to officially confirm another phenotype?</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191423">Todia P. Setiabudiawan, … , Andrew R. DiNardo, Reinout van Crevel</a> <a class='hide-for-small show-more' data-reveal-id='article45908-more' href='#'> <div class='article-authors'> Todia P. Setiabudiawan, … , Andrew R. DiNardo, Reinout van Crevel </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191423. <a href="https://doi.org/10.1172/JCI191423">https://doi.org/10.1172/JCI191423</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191423">Text</a> | <a href="/articles/view/191423/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191423' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191423/figure/1' ref='group' title='Different stages after exposure to Mtb. The TB resister phenotype is characterized by persistently negative IGRA/TST despite years-long exposure whereas early clearance reflects repeatedly negative IGRA results over a short period (e.g., 3 months) in the context of a well-defined exposure of TB household contacts to an index patient with a known Mtb isolate.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191423/small/JCI191423.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45908-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191423">Insights into protection against <i>Mycobacterium tuberculosis</i> infection: time to officially confirm another phenotype?</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191423">Text</a></li> <li><a class="button tiny" href="/articles/view/191423/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) remain elusive. In this issue of the JCI, Dallmann-Sauer and authors demonstrate that lack of tuberculin skin test (TST) and interferon γ release assay (IGRA) conversion among people with HIV despite years-long Mtb exposure is associated with alveolar lymphocytosis, including specific poly-cytotoxic T cells, and M1-type alveolar macrophages with a stronger ex vivo response to the pathogen. Studies in these rare individuals, termed “TB resisters” and in tuberculosis household contacts who are repeatedly IGRA negative in the months after a specific exposure event (known as “early clearers”) help elucidate manipulatable mechanisms to boost protection against Mtb infection.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Todia P. Setiabudiawan, Philip C. Hill, Andrew R. DiNardo, Reinout van Crevel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_article'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel5' name='research_article'> <strong></strong> <span class='toggle-icon'></span> Research Articles </a> <div class='content active' id='panel5'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post–myocardial infarction left ventricular remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/163730">Moydul Islam, … , Kartik Mani, Abhinav Diwan</a> <a class='hide-for-small show-more' data-reveal-id='article45892-more' href='#'> <div class='article-authors'> Moydul Islam, … , Kartik Mani, Abhinav Diwan </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e163730. <a href="https://doi.org/10.1172/JCI163730">https://doi.org/10.1172/JCI163730</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/163730">Text</a> | <a href="/articles/view/163730/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI163730' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/163730/figure/1' ref='group' title='Desmin, α-actinin, and actin and the serine 59 phosphorylated form of their chaperone protein, CRYAB, localize to protein aggregates in human ICM. (A) Representative immunohistochemical images from left ventricular myocardium of individuals evaluated as controls (donor) or patients with end-stage ICM stained for desmin, α-actinin, and actin. Arrows point to mislocalization of these proteins from their physiologic location on Z-discs and intercalated discs (desmin), Z-disc (α-actinin), and sarcomere (actin) in donor myocardium to protein aggregates in ICM myocardium. (B) Quantitation of striation score and aggregate score for desmin, α-actinin, and actin in ICM and donor hearts. n = 3-4 hearts/group. For striation scoring, normal localization of proteins got scored as 0, and abnormal striation or mislocalization of proteins was scored as 1. For scoring aggregates, absence of aggregates was scored as 0 and presence of aggregates was scored as 2. (C–G) Immunoblot (C) and quantitation (fold change as compared with donor mean) depicting total p62 (D), polyUb proteins (E), CRYAB (F), and pS59-CRYAB and pS45-CRYAB (G) in NP40-detergent-insoluble fractions from human hearts from patients with ICM and donors. Ponceau S staining is shown as loading control. (H–K) Immunoblot (H) and quantitation for p62 (I), CRYAB (J), and pS59-CRYAB and pS45-CRYAB (K) abundance in NP-40 detergent soluble biochemical fractions from human hearts as in C–G. GAPDH was used as loading control. n = 6 samples/group for C–K. *P < 0.05; **P < 0.01; ***P < 0.001 versus donor as control by t test.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/163000/163730/small/JCI163730.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45892-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post–myocardial infarction left ventricular remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/163730">Text</a></li> <li><a class="button tiny" href="/articles/view/163730/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart-failure syndromes remains mechanistically unexamined. We observed mislocalization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post–myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by the R120G mutation in the cognate chaperone protein CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine 59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phosphomimetic mutation of serine 59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates, and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knockin was sufficient to induce desmin mislocalization and myocardial protein aggregates, while S59A CRYAB knockin rescued left ventricular systolic dysfunction after myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine 59 phosphorylation and rescued post–myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Moydul Islam, David R. Rawnsley, Xiucui Ma, Walter Navid, Chen Zhao, Xumin Guan, Layla Foroughi, John T. Murphy, Honora Navid, Carla J. Weinheimer, Attila Kovacs, Jessica Nigro, Aaradhya Diwan, Ryan P. Chang, Minu Kumari, Martin E. Young, Babak Razani, Kenneth B. Margulies, Mahmoud Abdellatif, Simon Sedej, Ali Javaheri, Douglas F. Covey, Kartik Mani, Abhinav Diwan</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/175972">TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/175972">Yihui Li, … , Hao Wang, Ming Zhong</a> <a class='hide-for-small show-more' data-reveal-id='article45916-more' href='#'> <div class='article-authors'> Yihui Li, … , Hao Wang, Ming Zhong </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e175972. <a href="https://doi.org/10.1172/JCI175972">https://doi.org/10.1172/JCI175972</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/175972">Text</a> | <a href="/articles/view/175972/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI175972' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/175972/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/175000/175972/small/JCI175972.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45916-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/175972">TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/175972">Text</a></li> <li><a class="button tiny" href="/articles/view/175972/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in ER stress in chronic kidney disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress–induced tribble homolog 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX family transcription factor 2 (Runx2) and SMAD family member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic KO of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for CKD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177724">Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177724">Jiawen Yang, … , James A. DeCaprio, Megha Padi</a> <a class='hide-for-small show-more' data-reveal-id='article45909-more' href='#'> <div class='article-authors'> Jiawen Yang, … , James A. DeCaprio, Megha Padi </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e177724. <a href="https://doi.org/10.1172/JCI177724">https://doi.org/10.1172/JCI177724</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177724">Text</a> | <a href="/articles/view/177724/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177724' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/177724/figure/1' ref='group' title='MCPyV-perturbed cell model reveals signaling pathways altered during MCC development. IMR90 normal human fibroblasts expressing inducible MCPyV early region (ER) were subjected to bulk RNA-seq. (A) Principal component analysis (PCA) performed on all 13,870 expressed genes in the time series RNA-seq data. (B) The eigengenes of the 14 WGCNA modules were projected onto each time point and the modules were grouped by their dynamic patterns using hierarchical clustering. (C) Force-directed network of hub genes in the 14 WGCNA modules. The attraction forces between nodes were defined by the topological overlap matrix and were inversely proportional to the length of edges in the graph. (D) GO term enrichment analysis of each WGCNA gene module. The terms are ranked by adjusted P value, and the top-ranked terms are shown. Neuroendocrine related terms are highlighted in red, Wnt signaling related terms are highlighted in blue.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177724/small/JCI177724.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45909-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177724">Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177724">Text</a></li> <li><a class="button tiny" href="/articles/view/177724/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA-seq. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its antitumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and noncanonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a deeper understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jiawen Yang, James T. Lim, Paul Victor Santiago Raj, Marcelo G. Corona, Chen Chen, Hunain Khawaja, Qiong Pan, Gillian D. Paine-Murrieta, Rick G. Schnellmann, Denise J. Roe, Prafulla C. Gokhale, James A. DeCaprio, Megha Padi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/178550">TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/178550">Yu Zeng, … , Ye Song, Aidong Zhou</a> <a class='hide-for-small show-more' data-reveal-id='article45887-more' href='#'> <div class='article-authors'> Yu Zeng, … , Ye Song, Aidong Zhou </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e178550. <a href="https://doi.org/10.1172/JCI178550">https://doi.org/10.1172/JCI178550</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/178550">Text</a> | <a href="/articles/view/178550/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI178550' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/178550/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/178000/178550/small/JCI178550.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45887-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/178550">TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/178550">Text</a></li> <li><a class="button tiny" href="/articles/view/178550/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation–induced cell death, although the precise mechanisms involved remain unclear. Here, we report that loss of TNF receptor–associated factor 3 (TRAF3) in GBM critically regulated lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 was frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacted with enoyl-CoA hydratase 1 (ECH1), an enzyme that catalyzes the isomerization of unsaturated FAs (UFAs) and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impeded TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promoted the oxidation of UFAs, preferentially the PUFAs, and limited lipid peroxidation. Overexpression of TRAF3 enhanced the sensitivity of GBM to ferroptosis and anti–programmed death–ligand 1 (anti–PD-L1) immunotherapy in mice. Thus, the TRAF3/ECH1 axis played a key role in the metabolism of PUFAs and was crucial for lipid peroxidation damage and immune elimination in GBM.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jianyou Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179782">An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179782">Annegret Holm, … , Mathias Francois, Joyce Bischoff</a> <a class='hide-for-small show-more' data-reveal-id='article45917-more' href='#'> <div class='article-authors'> Annegret Holm, … , Mathias Francois, Joyce Bischoff </div> </a> <span class='article-published-at'> Published February 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e179782. <a href="https://doi.org/10.1172/JCI179782">https://doi.org/10.1172/JCI179782</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179782">Text</a> | <a href="/articles/view/179782/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179782' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/179782/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/179000/179782/small/JCI179782.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45917-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179782">An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179782">Text</a></li> <li><a class="button tiny" href="/articles/view/179782/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay of treatment, inhibits IH vessel formation via a β-adrenergic receptor-independent off-target effect of its R(+) enantiomer on endothelial SOX18 - a member of the SOX (SRY-related HMG-box) family of transcription factors. Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss and gain of function of SOX18 confirmed it is both necessary and sufficient for R(+) propranolol suppression of the MVP, including regulation of sterol regulatory element–binding protein 2 (SREBP2) and the rate-limiting enzyme HMG-CoA reductase (HMGCR). A biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear colocalization of SOX18 and SREBP2. Functional validation in a preclinical IH xenograft model revealed that statins — competitive inhibitors of HMGCR — efficiently suppress IH vessel formation. We propose an endothelial SOX18-MVP axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. The pleiotropic effects of R(+) propranolol and statins along the SOX18-MVP axis to disable an endothelial cell–specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Annegret Holm, Matthew S. Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun, Liang Sun, Pascal Brouillard, Ramrada Lekwuttikarn, Yanfei Qi, Joyce Teng, Miikka Vikkula, Harry Kozakewich, John B. Mulliken, Mathias Francois, Joyce Bischoff</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180802">Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180802">Yoon Mee Yang, … , Alexander M. Xu, Ekihiro Seki</a> <a class='hide-for-small show-more' data-reveal-id='article45888-more' href='#'> <div class='article-authors'> Yoon Mee Yang, … , Alexander M. Xu, Ekihiro Seki </div> </a> <span class='article-published-at'> Published February 13, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e180802. <a href="https://doi.org/10.1172/JCI180802">https://doi.org/10.1172/JCI180802</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180802">Text</a> | <a href="/articles/view/180802/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180802' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180802/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180802/small/JCI180802.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45888-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180802">Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180802">Text</a></li> <li><a class="button tiny" href="/articles/view/180802/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Steatotic liver enhances liver metastasis of colorectal cancer (CRC), but this process is not fully understood. Steatotic liver induced by a high-fat diet increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC mice had reduced steatotic liver–associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that low–molecular weight HA activates Yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 and M2 macrophages and CRC cells through CD44; these cells were associated with exhausted CD8+ T cells via programmed death–ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver–associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti–PD-1 antibody. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of CRC in the liver.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J. Pandol, Michael S. Lewis, Alexandra Gangi, Paul W. Noble, Dianhua Jiang, Akil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Sungyong You, Alexander M. Xu, Ekihiro Seki</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181517">ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non–small cell lung cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181517">Mengxia Jiao, … , Jie Gu, Ronghua Liu</a> <a class='hide-for-small show-more' data-reveal-id='article45904-more' href='#'> <div class='article-authors'> Mengxia Jiao, … , Jie Gu, Ronghua Liu </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e181517. <a href="https://doi.org/10.1172/JCI181517">https://doi.org/10.1172/JCI181517</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181517">Text</a> | <a href="/articles/view/181517/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181517' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/181517/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/181000/181517/small/JCI181517.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45904-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181517">ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non–small cell lung cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181517">Text</a></li> <li><a class="button tiny" href="/articles/view/181517/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) are emerging solid-tumor indicators of prognosis and response to immunotherapy. Considering that tumorigenesis requires metabolic reprogramming and subsequent TME remodeling, the discovery of TLS metabolic regulators is expected to produce immunotherapeutic targets. To identify such metabolic regulators, we constructed a metabolism-focused sgRNA library and performed an in vivo CRISPR screening in an orthotopic lung tumor mouse model. Combined with The Cancer Genome Atlas database analysis of TLS-related metabolic hub genes, we found that the loss of Acat1 in tumor cells sensitized tumors to anti-PD1 treatment, accompanied by increased TLS in the TME. Mechanistic studies revealed that ACAT1 resulted in mitochondrial protein hypersuccinylation in lung tumor cells and subsequently enhanced mitochondrial oxidative metabolism, which impeded TLS formation. Elimination of ROS by NAC or Acat1 knockdown promoted B cell aggregation and TLS construction. Consistently, data from tissue microassays of 305 patients with lung cancer showed that TLS were more abundant in non–small cell lung cancer (NSCLC) tissues with lower ACAT1 expression. Intratumoral ACAT1 expression was associated with poor immunotherapy outcomes in patients with NSCLC. In conclusion, our results identified ACAT1 as a metabolic regulator of TLS and a promising immunotherapeutic target in NSCLC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Mengxia Jiao, Yifan Guo, Hongyu Zhang, Haoyu Wen, Peng Chen, Zhiqiang Wang, Baichao Yu, Kameina Zhuma, Yuchen Zhang, Jingbo Qie, Yun Xing, Pengyuan Zhao, Zihe Pan, Luman Wang, Dan Zhang, Fei Li, Yijiu Ren, Chang Chen, Yiwei Chu, Jie Gu, Ronghua Liu</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181928">Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181928">Lu Sun, … , Suowen Xu, Jianping Weng</a> <a class='hide-for-small show-more' data-reveal-id='article45921-more' href='#'> <div class='article-authors'> Lu Sun, … , Suowen Xu, Jianping Weng </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e181928. <a href="https://doi.org/10.1172/JCI181928">https://doi.org/10.1172/JCI181928</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181928">Text</a> | <a href="/articles/view/181928/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181928' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/181928/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/181000/181928/small/JCI181928.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45921-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181928">Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181928">Text</a></li> <li><a class="button tiny" href="/articles/view/181928/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca2+ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell–specific Micu1 knockout mice (Micu1ECKO) and attenuated in endothelial cell–specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated development of atherosclerosis, while Micu1ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca2+ influx, thereby decreasing the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Lu Sun, Ruixue Leng, Monan Liu, Meiming Su, Qingze He, Zhidan Zhang, Zhenghong Liu, Zhihua Wang, Hui Jiang, Li Wang, Shuai Guo, Yiming Xu, Yuqing Huo, Clint L. Miller, Maciej Banach, Yu Huang, Paul C. Evans, Jaroslav Pelisek, Giovanni G. Camici, Bradford C. Berk, Stefan Offermanns, Junbo Ge, Suowen Xu, Jianping Weng</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182931">Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel</a> <a class='hide-for-small show-more' data-reveal-id='article45890-more' href='#'> <div class='article-authors'> Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel </div> </a> <span class='article-published-at'> Published February 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e182931. <a href="https://doi.org/10.1172/JCI182931">https://doi.org/10.1172/JCI182931</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182931">Text</a> | <a href="/articles/view/182931/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI182931' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/182931/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/182000/182931/small/JCI182931.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45890-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182931">Text</a></li> <li><a class="button tiny" href="/articles/view/182931/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer’s disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway I (UPS-I) events including (a) intracellular tau dephosphorylation, (b) caspase 3–mediated cleavage of tau (TauC3), and (c) membrane translocation of tau through binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and syndecan 3. In humans, the increase in CSF and plasma tau levels observed after wakefulness correlated with BT increases during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration and the preventative potential of thermal interventions.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I. Valencia, Audrey Yin, Hau-Tieng Wu, Jordan Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S. Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M. Rapoport, Indu Ayappa, Andrew W. Varga, Ankit Parekh, Ricardo S. Osorio, Steve Lacroix, Mark P. Burns, Brendan P. Lucey, Esther M. Blessing, Emmanuel Planel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183440">Endothelial cell–specific postnatal deletion of <i>Nos3</i> preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183440">Ruth A. Kelly, … , Darryl R. Overby, W. Daniel Stamer</a> <a class='hide-for-small show-more' data-reveal-id='article45899-more' href='#'> <div class='article-authors'> Ruth A. Kelly, … , Darryl R. Overby, W. Daniel Stamer </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e183440. <a href="https://doi.org/10.1172/JCI183440">https://doi.org/10.1172/JCI183440</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183440">Text</a> | <a href="/articles/view/183440/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183440' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183440/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183440/small/JCI183440.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45899-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183440">Endothelial cell–specific postnatal deletion of <i>Nos3</i> preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183440">Text</a></li> <li><a class="button tiny" href="/articles/view/183440/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Polymorphisms in Nos3 increase risk for glaucoma, the leading cause of irreversible blindness worldwide. A key modifiable risk factor for glaucoma is intraocular pressure (IOP), which is regulated by NO — a product of nitric oxide synthase 3 (encoded by Nos3) — in Schlemm’s canal of the conventional outflow pathway. We studied the effects of a conditional, endothelial cell–specific postnatal deletion of Nos3 (Endo-SclCre-ERT;Nos3fl/fl) on tissues of the outflow pathway. We observed that Cre-ERT expression spontaneously and gradually increased with time in vascular endothelia including in Schlemm’s canal, beginning at P10, with complete Nos3 deletion occurring around P90. Whereas outflow resistance was reduced in global Nos3-KO mice, outflow resistance and IOP in Endo-SclCre-ERT;Nos3fl/fl mice were normal. We observed — coincident with Nos3 deletion — recruitment of macrophages to and induction of both ELAM1 and NOS2 expression by endothelia in the distal portion of the outflow pathway, which increased vessel diameter. These adjustments reduced outflow resistance to maintain IOP in these Endo-SclCre-ERT;Nos3fl/fl mice. Selective inhibition of iNOS by 1400W resulted in narrowing of distal vessels and IOP elevation. Together, the results emphasize the pliability of the outflow system and the importance of NO signaling in IOP control, and imply an substantial role for macrophages in IOP homeostasis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ruth A. Kelly, Megan S. Kuhn, Ester Reina-Torres, Revathi Balasubramanian, Kristin M. Perkumas, Guorong Li, Takamune Takahashi, Simon W.M. John, Michael H. Elliott, Darryl R. Overby, W. Daniel Stamer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183559">Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183559">Jiale Chen, … , Qiang Liu, Jie Zhou</a> <a class='hide-for-small show-more' data-reveal-id='article45893-more' href='#'> <div class='article-authors'> Jiale Chen, … , Qiang Liu, Jie Zhou </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e183559. <a href="https://doi.org/10.1172/JCI183559">https://doi.org/10.1172/JCI183559</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183559">Text</a> | <a href="/articles/view/183559/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183559' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183559/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183559/small/JCI183559.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45893-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183559">Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183559">Text</a></li> <li><a class="button tiny" href="/articles/view/183559/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation–mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184743"><i>HoxBlinc</i> lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184743">Karina Hamamoto, … , Mingjiang Xu, Suming Huang</a> <a class='hide-for-small show-more' data-reveal-id='article45913-more' href='#'> <div class='article-authors'> Karina Hamamoto, … , Mingjiang Xu, Suming Huang </div> </a> <span class='article-published-at'> Published January 30, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e184743. <a href="https://doi.org/10.1172/JCI184743">https://doi.org/10.1172/JCI184743</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184743">Text</a> | <a href="/articles/view/184743/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184743' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/184743/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/184000/184743/small/JCI184743.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45913-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184743"><i>HoxBlinc</i> lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184743">Text</a></li> <li><a class="button tiny" href="/articles/view/184743/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of homeobox (HOX) genes, underlying mechanisms remain elusive. Here, we report that the Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion–driven leukemias. HoxBlinc chromatin occupancies led to elevated mixed-lineage leukemia 1 (MLL1) recruitment and aberrant homeotic topologically associated domains (TADs) that enhanced chromatin accessibilities and activated homeotic/hematopoietic oncogenes. HoxBlinc depletion in NUP98 fusion–driven leukemia impaired HoxBlinc binding, TAD integrity, MLL1 recruitment, and the MLL1-driven chromatin signature within HoxBlinc-defined TADs in a CCCTC-binding factor–independent (CTCF-independent) manner, leading to inhibited homeotic/leukemic oncogenes that mitigated NUP98 fusion–driven leukemogenesis in xenografted mouse models. Mechanistically, HoxBlinc overexpression in the mouse hematopoietic compartment induced leukemias resembling those in NUP98-PHF23–knockin (KI) mice via enhancement of HoxBlinc chromatin binding, TAD formation, and Hox gene aberration, leading to expansion of hematopoietic stem and progenitor cell and myeloid/lymphoid cell subpopulations. Thus, our studies reveal a CTCF-independent role of HoxBlinc in leukemic TAD organization and oncogene-regulatory networks.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Karina Hamamoto, Ganqian Zhu, Qian Lai, Julia Lesperance, Huacheng Luo, Ying Li, Nupur Nigam, Arati Sharma, Feng-Chun Yang, David Claxton, Yi Qiu, Peter D. Aplan, Mingjiang Xu, Suming Huang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185489">Rapamycin enhances CAR-T control of HIV replication and reservoir elimination in vivo</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185489">Wenli Mu, … , Scott G. Kitchen, Anjie Zhen</a> <a class='hide-for-small show-more' data-reveal-id='article45910-more' href='#'> <div class='article-authors'> Wenli Mu, … , Scott G. Kitchen, Anjie Zhen </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e185489. <a href="https://doi.org/10.1172/JCI185489">https://doi.org/10.1172/JCI185489</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185489">Text</a> | <a href="/articles/view/185489/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185489' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185489/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185489/small/JCI185489.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45910-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185489">Rapamycin enhances CAR-T control of HIV replication and reservoir elimination in vivo</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185489">Text</a></li> <li><a class="button tiny" href="/articles/view/185489/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Chimeric antigen receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and nonhuman primates demonstrate that hematopoietic stem cells (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional antiviral CAR-T cells that reduce viral rebound after antiretroviral therapy (ART) withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle to sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low-dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondrial respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells, and improved CAR-T control of viral replication. RNA-sequencing analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound after ART and reduced HIV reservoir compared with those treated with CAR-HSCs alone. These findings suggest that HSC-based anti-HIV CAR-T cells combined with rapamycin treatment are a promising approach for treating persistent inflammation and improving immune control of HIV replication.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Wenli Mu, Shallu Tomer, Jeffrey Harding, Nandita Kedia, Valerie Rezek, Ethan Cook, Vaibahavi Patankar, Mayra A. Carrillo, Heather Martin, Hwee Ng, Li Wang, Matthew D. Marsden, Scott G. Kitchen, Anjie Zhen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185796">Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185796">Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang</a> <a class='hide-for-small show-more' data-reveal-id='article45935-more' href='#'> <div class='article-authors'> Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang </div> </a> <span class='article-published-at'> Published February 12, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e185796. <a href="https://doi.org/10.1172/JCI185796">https://doi.org/10.1172/JCI185796</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185796">Text</a> | <a href="/articles/view/185796/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185796' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185796/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185796/small/JCI185796.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45935-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185796">Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185796">Text</a></li> <li><a class="button tiny" href="/articles/view/185796/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, noncell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Salvatore Marco Caruso, Xuan Cui, Brian M. Robbings, Noah Heapes, Aykut Demirkol, Bruna Lopes Da Costa, Daniel T. Hass, Peter M.J. Quinn, Jianhai Du, James B. Hurley, Stephen H. Tsang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186416">MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186416">Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper</a> <a class='hide-for-small show-more' data-reveal-id='article45897-more' href='#'> <div class='article-authors'> Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e186416. <a href="https://doi.org/10.1172/JCI186416">https://doi.org/10.1172/JCI186416</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186416">Text</a> | <a href="/articles/view/186416/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186416' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186416/figure/1' ref='group' title='Exogenous MBNL1 and MBNL2 are overexpressed in ventricles and atria of CUG960 +dox mice by AAV9 delivery. (A) Diagram of the pAAV vectors used to express control tdTomato protein (pAAV-tdTomato), 3xFLAG-MBNL1, and 3xMYC-MBNL2. (B) Diagram of the experimental design including time points and assays. (C) Cardiac ventricular and atrial protein expression was evaluated by Western blotting. n = 3 animals per cohort.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186416/small/JCI186416.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45897-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186416">MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186416">Text</a></li> <li><a class="button tiny" href="/articles/view/186416/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and misregulated alternative splicing and gene expression. While robust, the rescue was partial compared with reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J. Johnson, Ayrea E. Hurley, William R. Lagor, Zheng Xia, Thomas A. Cooper</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/187024">Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187024">Kang Sun, … , Xueli Bai, Tingbo Liang</a> <a class='hide-for-small show-more' data-reveal-id='article45901-more' href='#'> <div class='article-authors'> Kang Sun, … , Xueli Bai, Tingbo Liang </div> </a> <span class='article-published-at'> Published January 30, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e187024. <a href="https://doi.org/10.1172/JCI187024">https://doi.org/10.1172/JCI187024</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187024">Text</a> | <a href="/articles/view/187024/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI187024' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/187024/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/187000/187024/small/JCI187024.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45901-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187024">Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187024">Text</a></li> <li><a class="button tiny" href="/articles/view/187024/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. “Immune cold” PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxing Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188016"><i>Mycobacterium tuberculosis</i> resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188016">Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr</a> <a class='hide-for-small show-more' data-reveal-id='article45907-more' href='#'> <div class='article-authors'> Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr </div> </a> <span class='article-published-at'> Published January 21, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e188016. <a href="https://doi.org/10.1172/JCI188016">https://doi.org/10.1172/JCI188016</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188016">Text</a> | <a href="/articles/view/188016/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188016' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188016/figure/1' ref='group' title='Resisters have higher lymphocyte proportions in cells obtained by BAL compared with LTBI. (A) Schematic representation of the study design. BAL cells were obtained from all study participants and scRNA-Seq was conducted at 6 hours and 24 hours in the presence and absence of Mtb infection. Gene-expression data were derived both for uninfected (defined as baseline) and infected BAL cells. Analysis of scRNA-Seq data was used to estimate BAL cell identities and proportions and to perform DE analysis. Created with BioRender.com. (B) UMAP of the scRNA-Seq data from the BAL cells of all subjects identified myeloid cells and lymphocytes as 2 main populations. (C) Gene expression of canonical markers for macrophages (LYZ and CD68), DCs (LAMP3), leukocytes (PTPRC [CD45]), T cells (CD3D), and B cells (MS4A1). Higher expressions are shown by darker colors in the UMAP. (D) Density of cells obtained from LTBI and resister participants. Dashed-line circles indicate the BAL lymphocytes in the 2 groups. Yellow and dark blue colors indicate the highest and lowest density of cells in the UMAP, respectively. UMAPs included samples irrespective of infection status and incubation time point. (E) Box plot of lymphocyte proportions (%) in BAL cells obtained from resister and LTBI participants. Each dot represents the average lymphocyte percentage obtained from the scRNA-Seq libraries per subject. (F) Lymphocyte proportion (%) in PBMCs for the same resister and LTBI participants.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188016/small/JCI188016.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45907-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188016"><i>Mycobacterium tuberculosis</i> resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188016">Text</a></li> <li><a class="button tiny" href="/articles/view/188016/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained.METHODS We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were tuberculin skin test (TST) and IFN-γ release assay (IGRA) positive (called LTBI) and 6 who were persistently TST and IGRA negative (called resisters).RESULTS Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that coexpressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (poly-CTL) overexpressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only intraepithelial lymphocyte-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6 hours after infection while at 24 hours after infection, AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24 hours after infection, only AM from resisters displayed an upregulation of MHC class I polypeptide–related sequence A (MICA) transcripts, which encode an activating ligand for poly-CTL.CONCLUSION These results suggest that poly-CTL and M1-like pre-activated AM mediate the resister phenotype in PWH.FUNDING National Institutes of Health. Canadian Institutes of Health Research. Digital Research Alliance of Canada. French National Research Agency. French National Agency for Research on AIDS and Viral Hepatitis. St. Giles Foundation. General Atlantic Foundation. South African Medical Research Council Centre for Tuberculosis Research.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Monica Dallmann-Sauer, Vinicius M. Fava, Stephanus T. Malherbe, Candice E. MacDonald, Marianna Orlova, Elouise E. Kroon, Aurélie Cobat, Stéphanie Boisson-Dupuis, Eileen G. Hoal, Laurent Abel, Marlo Möller, Jean-Laurent Casanova, Gerhard Walzl, Nelita Du Plessis, Erwin Schurr</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/189197">Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/189197">Shike Wang, … , Xiaochao Tan, Jonathan M. Kurie</a> <a class='hide-for-small show-more' data-reveal-id='article45906-more' href='#'> <div class='article-authors'> Shike Wang, … , Xiaochao Tan, Jonathan M. Kurie </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e189197. <a href="https://doi.org/10.1172/JCI189197">https://doi.org/10.1172/JCI189197</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/189197">Text</a> | <a href="/articles/view/189197/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI189197' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/189197/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/189000/189197/small/JCI189197.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45906-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/189197">Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/189197">Text</a></li> <li><a class="button tiny" href="/articles/view/189197/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of the Col6 heterotrimeric molecule, as a candidate LH2 substrate. In gain- and loss-of-function studies, high Col6a3 levels increased tumor growth and metastatic activity and enhanced the proliferative, migratory, and invasive activities of LUAD cells. LH2 coimmunoprecipitated with Col6a3, and LH2 glucosylated Col6 in an in vitro reaction. Glucosylation increased the integrin-binding and promigratory activities of Col6 in LUAD cells. Col6a3 K2049 was deglucosylated in GGT-inactive tumor samples, and mutagenesis of Col6a3 K2049 phenocopied Col6a3 deficiency or LH2 GGT domain inactivation in LUAD cells. Thus, LH2 glucosylates Col6 to drive LUAD progression. These findings show that the GGT domain of LH2 is protumorigenic, identify Col6 as a candidate effector, and provide a rationale to develop pharmacological strategies that target LH2’s GGT domain in cancer cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K. Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M. Kurie</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <hr> <h4> In-Press Preview <small>- <a title="View more In-Press Preview articles" href="/in-press-preview">More</a></small> </h4> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181659">ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45940-more' href='#'> <div class='article-abstract'> Telomere biology disorders (TBD) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/23"><span class='label-specialty'> Hematology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181659' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45940-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181659">ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181659">Text</a></li> <li><a class="button tiny" href="/articles/view/181659/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Telomere biology disorders (TBD) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 166 pediatric and adult TBD patients. 47.6% of patients (28.8% of children, 56.1% of adults) had clonal hematopoiesis. Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly U2AF1 p.S34), and chromosomal alterations (20.2%), including 1q gain (5.9%). Somatic variants affecting the DNA damage response (DDR) were identified in 21.5% of patients, including 20 presumed loss-of-function variants in ATM. Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell growth assays, we demonstrate telomere dysfunction-induced activation of ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic ATM variants, selectively improved TBD cell fitness by allowing cells to bypass DDR-mediated senescence without detectably inducing chromosomal instability. Our results indicate that ATM-dependent DDR induced by telomere dysfunction is a key contributor to TBD pathogenesis and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Christopher M. Sande, Stone Chen, Dana V. Mitchell, Ping Lin, Diana M. Abraham, Jessie M. Cheng, Talia Gebhard, Rujul J. Deolikar, Colby Freeman, Mary Zhou, Sushant Kumar, Michael Bowman, Robert L. Bowman, Shannon Zheng, Bolormaa Munkhbileg, Qijun Chen, Natasha L. Stanley, Kathy Guo, Ajibike Lapite, Ryan Hausler, Deanne M. Taylor, James Corines, Jennifer J.D. Morrissette, David B. Lieberman, Guang Yang, Olga Shestova, Saar Gill, Jiayin Zheng, Kelcy Smith-Simmer, Lauren G. Banaszak, Kyle N. Shoger, Erica F. Reinig, Madilynn Peterson, Peter Nicholas, Amanda J. Walne, Inderjeet Dokal, Justin P. Rosenheck, Karolyn A. Oetjen, Daniel C. Link, Andrew E. Gelman, Christopher R. Reilly, Ritika Dutta, R. Coleman Lindsley, Karyn J. Brundige, Suneet Agarwal, Alison A. Bertuch, Jane E. Churpek, Laneshia K. Tague, F. Brad Johnson, Timothy S. Olson, Daria V. Babushok</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184115">SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45938-more' href='#'> <div class='article-abstract'> The Wnt/β-catenin pathway regulates expression of the SOX9 gene, which encodes SRY-box transcription factor 9, a differentiation factor and potential β-catenin regulator. Because APC tumor... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/21"><span class='label-specialty'> Gastroenterology </span> </a><a href="/tags/22"><span class='label-specialty'> Genetics </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184115' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45938-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184115">SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184115">Text</a></li> <li><a class="button tiny" href="/articles/view/184115/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The Wnt/β-catenin pathway regulates expression of the SOX9 gene, which encodes SRY-box transcription factor 9, a differentiation factor and potential β-catenin regulator. Because APC tumor suppressor defects in ~80% of colorectal cancers (CRCs) activate the Wnt/β-catenin pathway, we studied SOX9 inactivation in CRC biology. Compared to effects of Apc inactivation in mouse colon tumors, combined Apc and Sox9 inactivation instigated more invasive tumors with epithelial-mesenchymal transition (EMT) and SOX2 stem cell factor upregulation. In an independent mouse CRC model with combined Apc, Kras, and Trp53 defects, Sox9 inactivation promoted SOX2 induction and distant metastases. About 20% of 171 human CRCs showed loss of SOX9 protein expression, which correlated with higher tumor grade. In an independent group of 376 CRC patients, low SOX9 gene expression was linked to poor survival, earlier age at diagnosis, and increased lymph node involvement. SOX9 expression reductions in human CRC were linked to promoter methylation. EMT pathway gene expression changes were prominent in human CRCs with low SOX9 expression and in a mouse cancer model with high SOX2 expression. Our results indicate SOX9 has tumor suppressor function in CRC; its loss may promote progression, invasion, and poor prognosis by enhancing EMT and stem cell phenotypes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ying Feng, Ningxin Zhu, Karan Bedi, Jinju Li, Chamila Perera, Maranne Green, Naziheh Assarzadegan, Yali Zhai, Qingzhi Liu, Veerabhadran Baladandayuthapani, Jason R. Spence, Kathleen R. Cho, Eric R. Fearon</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181243">Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45937-more' href='#'> <div class='article-abstract'> Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/21"><span class='label-specialty'> Gastroenterology </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181243' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45937-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181243">Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181243">Text</a></li> <li><a class="button tiny" href="/articles/view/181243/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse metabolites that feature unique mechanisms of interaction with host targets, yet the role of many metabolites in CRC remains poorly understood. In this study, the microbial metabolite 4-hydroxybenzeneacetic acid (4-HPA) promoted the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment, consequently inhibiting the anti-tumor response of CD8+ T cells and promoting CRC progression in vivo. Mechanistically, 4-HPA activates the JAK2/STAT3 pathway, which upregulates CXCL3 transcription, thereby recruiting PMN-MDSCs to the CRC microenvironment. Selective knockdown of CXCL3 re-sensitized tumors to anti-PD1 immunotherapy in vivo. Chlorogenic acid (CGA) reduces the production of 4-HPA by microbiota, likewise abolishing 4-HPA-mediated immunosuppression. The 4-HPA content in CRC tissues was notably increased in patients with advanced CRC. Overall, the gut microbiome uses 4-HPA as a messenger to control chemokine-dependent accumulation of PMN-MDSC cells and regulate anti-tumor immunity in CRC. Our findings provide a scientific basis for establishing clinical intervention strategies to reverse the tumor immune microenvironment and improve the efficacy of immunotherapy by reducing the interaction between intestinal microbiota, tumor cells and tumor immune cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Qing Liao, Ximing Zhou, Ling Wu, Yuyi Yang, Xiaohui Zhu, Hangyu Liao, Yujie Zhang, Weidong Lian, Feifei Zhang, Hui Wang, Yanqing Ding, Liang Zhao</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186939">Immune repertoire profiling uncovers pervasive T-cell clonal expansions in benign prostatic hyperplasia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45928-more' href='#'> <div class='article-abstract'> </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/127"><span class='label-article-type'> Research Letter </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/27"><span class='label-specialty'> Inflammation </span> </a><a href="/tags/37"><span class='label-specialty'> Reproductive biology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186939' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45928-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186939">Immune repertoire profiling uncovers pervasive T-cell clonal expansions in benign prostatic hyperplasia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186939">Text</a></li> <li><a class="button tiny" href="/articles/view/186939/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p> </p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Anna S. Pollack, Christian A. Kunder, Chandler C. Ho, Josephine Chou, Andrew J. Pollack, Rachel L. P. Geisick, Bing M. Zhang, Robert B. West, James D. Brooks, Jonathan R. Pollack</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180570">Hyaluronan network remodeling by ZEB1 and ITIH2 enhances the motility and invasiveness of cancer cells</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45931-more' href='#'> <div class='article-abstract'> Hyaluronan (HA) in the extracellular matrix promotes epithelial-to-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/16"><span class='label-specialty'> Cell biology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180570' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45931-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180570">Hyaluronan network remodeling by ZEB1 and ITIH2 enhances the motility and invasiveness of cancer cells</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180570">Text</a></li> <li><a class="button tiny" href="/articles/view/180570/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Hyaluronan (HA) in the extracellular matrix promotes epithelial-to-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-alpha-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when co-cultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and invasion of lung cancer cells. Furthermore, ZEB1 facilitates alternative splicing and isoform expression of CD44, an HA receptor, and CD44 knockdown suppresses the motility and invasiveness of lung cancer cells. Using a deep learning-based drug-target interaction algorithm, we identified an ITIH2 inhibitor (sincalide) that inhibited HA matrix formation and migration of lung cancer cells, preventing metastatic colonization of lung cancer cells in mouse models. These findings suggest that ZEB1 remodels the HA network in the TME through the regulation of ITIH2, HAS2, and CD44, presenting a strategy for targeting this network to suppress lung cancer progression.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sieun Lee, Jihye Park, Seongran Cho, Eun Ju Kim, Seonyeong Oh, Younseo Lee, Sungsoo Park, Keunsoo Kang, Dong Hoon Shin, Song Yi Ko, Jonathan M. 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