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No commercial re-use. See rights and permissions. Published by BMJ." /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Relation" content="10.1136/gutjnl-2024-333213" /> <meta name="DC.Description" content="Although numerous compounds that target individual or multiple cells or pathways have demonstrated antifibrotic potential, the reality is that only a small number of candidates have progressed successfully to the clinical trials phase. It seems plausible that the development of antifibrotic therapies focusing on the removal of fibrosis-causing agents and factors affecting hepatic stellate cell (HSC) activation might hold promise for reducing and preventing liver disease. Moreover, these therapies need to be safe with little or no hepatotoxicity and/or adverse effects. In liver homoeostasis, transforming growth factor-beta (TGF-β) is secreted in a biologically inactive, the so-called latent TGF-β form (LTGF-β) associated in a non-covalent complex with the extracellular matrix (ECM).1 In response to injury, local LTGF-β complexes are converted into active TGF-β. Activation of LTGF-β is mediated by several signals, including integrins, thrombospondin, proteases and reactive oxygen species.2 During liver fibrosis, TGF-β acts as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of HSC, a central event in liver fibrogenesis and ECM production.3 Therefore, the regulation of locally activated TGF-β levels might be an excellent therapeutic target for liver fibrogenesis. ECM protein-1 (ECM1) was recently identified2 as a critical gatekeeper in the healthy liver, contributing to normal architecture and physiological homoeostasis of cell–cell communication by …" /> <meta name="DC.Contributor" content="Isabel Fabregat" /> <meta name="DC.Contributor" content="Francisco Javier Cubero" /> <meta name="article:published_time" content="2024-10-23" /> <meta name="article:section" content="Commentary" /> <meta name="citation_title" content="ECM1: a novel matricellular protein with promising antifibrotic potential" /> <meta name="citation_journal_title" content="Gut" /> <meta name="citation_publisher" content="BMJ Publishing Group" /> <meta name="citation_publication_date" content="2024/10/23" /> <meta name="citation_mjid" content="gutjnl;gutjnl-2024-333455v1" /> <meta name="citation_id" content="gutjnl-2024-333455v1" /> <meta name="citation_public_url" content="https://gut.bmj.com/content/early/2024/10/23/gutjnl-2024-333455" /> <meta name="citation_abstract_html_url" content="https://gut.bmj.com/content/early/2024/10/23/gutjnl-2024-333455.abstract" /> <meta name="citation_full_html_url" content="https://gut.bmj.com/content/early/2024/10/23/gutjnl-2024-333455.full" /> <meta name="citation_pdf_url" content="https://gut.bmj.com/content/gutjnl/early/2024/10/23/gutjnl-2024-333455.full.pdf" /> <meta name="citation_issn" content="0017-5749" /> <meta name="citation_issn" content="1468-3288" /> <meta name="citation_doi" content="10.1136/gutjnl-2024-333455" /> <meta name="citation_pmid" content="39448253" /> <meta name="citation_article_type" content="Article Commentary" /> <meta name="citation_section" content="Commentary" /> <meta name="citation_author" content="Isabel Fabregat" /> <meta name="citation_author_institution" content="TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet" /> <meta name="citation_author_institution" content="Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD)" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0003-0136-8440" /> <meta name="citation_author" content="Francisco Javier Cubero" /> <meta name="citation_author_institution" content="Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD)" /> <meta name="citation_author_institution" content="Immunology, Ophthalmology and ENT" /> <meta name="citation_author_institution" content="Complutense University of Madrid Faculty of Medicine" /> <meta name="citation_author_institution" content="Health Research Institute Gregorio Marañón (IiSGM)" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0003-1499-650X" /> <meta name="citation_reference" content="citation_journal_title=Front Physiol;citation_title=Biological Significance of Local TGF-β Activation in Liver Diseases;citation_volume=3;citation_year=2012" /> <meta name="citation_reference" content="citation_journal_title=JHEP Rep;citation_title=Transforming growth factor β latency: a mechanism of cytokine storage and signalling regulation in liver homeostasis and disease;citation_volume=4;citation_year=2022" /> <meta name="citation_reference" content="citation_journal_title=FEBS J;citation_author=I. Fabregat;citation_author=J. Moreno-Càceres;citation_author=A. Sánchez;citation_title=TGF-β signalling and liver disease;citation_pages=2219-32;citation_volume=283;citation_year=2016;citation_pmid=26807763;citation_doi=10.1111/febs.13665" /> <meta name="citation_reference" content="citation_journal_title=Gastroenterology;citation_author=W. Fan;citation_author=T. Liu;citation_author=W. Chen;citation_title=ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice;citation_pages=1352-67;citation_volume=157;citation_year=2019;citation_pmid=31362006;citation_doi=10.1053/j.gastro.2019.07.036" /> <meta name="citation_reference" content="citation_journal_title=Gut;citation_title=ECM1 attenuates hepatic fibrosis by interfering with mediators of latent tgf-β1 activation;citation_year=2024" /> <meta name="citation_reference" content="citation_journal_title=Hepatol Res;citation_author=Y. Li;citation_author=CP. Turpin;citation_author=S. Wang;citation_title=Role of thrombospondin 1 in liver diseases;citation_pages=186-93;citation_volume=47;citation_year=2017;citation_pmid=27492250;citation_doi=10.1111/hepr.12787" /> <meta name="citation_reference" content="citation_journal_title=Hepatology (Baltimore, Md.);citation_journal_abbrev=Hepatology;citation_author=K. Bourd-Boittin;citation_author=D. Bonnier;citation_author=A. Leyme;citation_title=Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta.;citation_pages=2173-2184;citation_volume=54;citation_year=2011;citation_issue=6;citation_pmid=21826695;citation_doi=10.1002/hep.24598" /> <meta name="twitter:title" content="ECM1: a novel matricellular protein with promising antifibrotic potential" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:image" content="https://gut.bmj.com/sites/default/files/highwire/gutjnl/73/12.cover-source.jpg" /> <meta name="twitter:description" content="Although numerous compounds that target individual or multiple cells or pathways have demonstrated antifibrotic potential, the reality is that only a small number of candidates have progressed successfully to the clinical trials phase. It seems plausible that the development of antifibrotic therapies focusing on the removal of fibrosis-causing agents and factors affecting hepatic stellate cell (HSC) activation might hold promise for reducing and preventing liver disease. Moreover, these therapies need to be safe with little or no hepatotoxicity and/or adverse effects. In liver homoeostasis, transforming growth factor-beta (TGF-β) is secreted in a biologically inactive, the so-called latent TGF-β form (LTGF-β) associated in a non-covalent complex with the extracellular matrix (ECM).1 In response to injury, local LTGF-β complexes are converted into active TGF-β. Activation of LTGF-β is mediated by several signals, including integrins, thrombospondin, proteases and reactive oxygen species.2 During liver fibrosis, TGF-β acts as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of HSC, a central event in liver fibrogenesis and ECM production.3 Therefore, the regulation of locally activated TGF-β levels might be an excellent therapeutic target for liver fibrogenesis. ECM protein-1 (ECM1) was recently identified2 as a critical gatekeeper in the healthy liver, contributing to normal architecture and physiological homoeostasis of cell–cell communication by …" /> <meta name="og-title" property="og:title" content="ECM1: a novel matricellular protein with promising antifibrotic potential" /> <meta name="og-url" property="og:url" content="https://gut.bmj.com/content/early/2024/10/23/gutjnl-2024-333455" /> <meta name="og-site-name" property="og:site_name" content="Gut" /> <meta name="og-description" property="og:description" content="Although numerous compounds that target individual or multiple cells or pathways have demonstrated antifibrotic potential, the reality is that only a small number of candidates have progressed successfully to the clinical trials phase. It seems plausible that the development of antifibrotic therapies focusing on the removal of fibrosis-causing agents and factors affecting hepatic stellate cell (HSC) activation might hold promise for reducing and preventing liver disease. Moreover, these therapies need to be safe with little or no hepatotoxicity and/or adverse effects. In liver homoeostasis, transforming growth factor-beta (TGF-β) is secreted in a biologically inactive, the so-called latent TGF-β form (LTGF-β) associated in a non-covalent complex with the extracellular matrix (ECM).1 In response to injury, local LTGF-β complexes are converted into active TGF-β. Activation of LTGF-β is mediated by several signals, including integrins, thrombospondin, proteases and reactive oxygen species.2 During liver fibrosis, TGF-β acts as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of HSC, a central event in liver fibrogenesis and ECM production.3 Therefore, the regulation of locally activated TGF-β levels might be an excellent therapeutic target for liver fibrogenesis. 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class="xref-aff">4</span></li></ol><ol class="affiliation-list"><li class="aff"><address><sup>1</sup><span class="institution">TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet</span>, <span class="addr-line">Barcelona</span>, Spain</address></li><li class="aff"><address><sup>2</sup><span class="institution">Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD)</span>, <span class="addr-line">Madrid</span>, Spain</address></li><li class="aff"><address><sup>3</sup><span class="institution">Immunology, Ophthalmology and ENT</span>, <span class="institution">Complutense University of Madrid Faculty of Medicine</span>, <span class="addr-line">Madrid</span>, Spain</address></li><li class="aff"><address><sup>4</sup><span class="institution">Health Research Institute Gregorio Marañón (IiSGM)</span>, <span class="addr-line">Madrid</span>, Spain</address></li></ol><ol class="corresp-list"><li class="corresp" id="corresp-1"><span class="corresp-label">Correspondence to</span> Professor Francisco Javier Cubero; <span class="em-link"><span class="em-addr">fcubero{at}ucm.es</span></span></li></ol></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup abstract-with-bc" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" id="content-block" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="related-urls"></span></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-custom pane-1" > <div class="pane-content"> <p><a href="https://doi.org/10.1136/gutjnl-2024-333455" target="_new">https://doi.org/10.1136/gutjnl-2024-333455</a></p> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-altmetrics" > <h2 class="pane-title">Statistics from Altmetric.com</h2> <div class="pane-content"> <div 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You will be able to get a quick price and instant permission to reuse the content in many different ways.</p> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-panels-ajax-pane-content permissions-box pane-highwire-permission-link" id="request-permissions"> <h2 class="pane-title"><span class='panels-ajax-pane-title' data-pid='new-70fd4c70-563e-4b94-ae3b-2a97f3980c13'></span></h2> <div class="pane-content"> <div class='panels-ajax-pane panels-ajax-pane-new-70fd4c70-563e-4b94-ae3b-2a97f3980c13' data-pid='new-70fd4c70-563e-4b94-ae3b-2a97f3980c13'></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article extract-view"><span class="highwire-journal-article-marker-start"></span><ul class="kwd-group"><li class="kwd"><a href="/keyword/hepatic-fibrosis" class="hw-term hw-article-keyword hw-article-keyword-hepatic-fibrosis" rel="nofollow">HEPATIC FIBROSIS</a></li><li class="kwd"><a href="/keyword/tgf-beta" class="hw-term hw-article-keyword hw-article-keyword-tgf-beta" rel="nofollow">TGF-BETA</a></li><li class="kwd"><a href="/keyword/extracellular-matrix" class="hw-term hw-article-keyword hw-article-keyword-extracellular-matrix" rel="nofollow">EXTRACELLULAR MATRIX</a></li><li class="kwd"><a href="/keyword/hepatic-stellate-cell" class="hw-term hw-article-keyword hw-article-keyword-hepatic-stellate-cell" rel="nofollow">HEPATIC STELLATE CELL</a></li><li class="kwd"><a href="/keyword/chronic-liver-disease" class="hw-term hw-article-keyword hw-article-keyword-chronic-liver-disease" rel="nofollow">CHRONIC LIVER DISEASE</a></li></ul><p id="p-1">Although numerous compounds that target individual or multiple cells or pathways have demonstrated antifibrotic potential, the reality is that only a small number of candidates have progressed successfully to the clinical trials phase. It seems plausible that the development of antifibrotic therapies focusing on the removal of fibrosis-causing agents and factors affecting hepatic stellate cell (HSC) activation might hold promise for reducing and preventing liver disease. Moreover, these therapies need to be safe with little or no hepatotoxicity and/or adverse effects.</p><p id="p-2">In liver homoeostasis, transforming growth factor-beta (TGF-β) is secreted in a biologically inactive, the so-called latent TGF-β form (LTGF-β) associated in a non-covalent complex with the extracellular matrix (ECM).<span class="xref-bibr">1</span> In response to injury, local LTGF-β complexes are converted into active TGF-β. Activation of LTGF-β is mediated by several signals, including integrins, thrombospondin, proteases and reactive oxygen species.<span class="xref-bibr">2</span> During liver fibrosis, TGF-β acts as a master profibrogenic cytokine in promoting activation and myofibroblastic differentiation of HSC, a central event in liver fibrogenesis and ECM production.<span class="xref-bibr">3</span> Therefore, the regulation of locally activated TGF-β levels might be an excellent therapeutic target for liver fibrogenesis.</p><p id="p-3">ECM protein-1 (ECM1) was recently identified<span class="xref-bibr">2</span> as a critical gatekeeper in the healthy liver, contributing to normal architecture and physiological homoeostasis of cell–cell communication by … </p><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div><a href="https://gut.bmj.com/content/early/2024/10/23/gutjnl-2024-333455.full" class="hw-link hw-link-article-full-text" data-icon-position="" 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HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679.</span></p></li><li class="fn-conflict" id="fn-4"><p id="p-14"><span class="fn-label">Competing interests</span> None declared.</p></li><li class="fn-other" id="fn-5"><p id="p-15"><span class="fn-label">Provenance and peer review</span> Commissioned; internally peer reviewed.</p></li></ul></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-dfp-pane" > <div class="pane-content"> <div id="dfp-ad-mpu-wrapper" class="dfp-tag-wrapper"> <div id="dfp-ad-mpu" class="dfp-tag-wrapper"> <script type="text/javascript"> googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); </script> </div> </div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-atom bmjj-linked-articles" id="linked-articles"> <h2 class="pane-title">Linked Articles</h2> <div class="pane-content"> <div class="highwire-atom-data-bmjj-linked-articles field field-highwire-atom-data 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