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Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1\/THY1\n                    <jats:sup>+<\/jats:sup>\n                    myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.\n                  <\/jats:p>","DOI":"10.7554\/elife.95185","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T12:25:56Z","timestamp":1720441556000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.95185","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-7703","authenticated-orcid":true,"given":"Paul","family":"Horn","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/014ja3n03","id-type":"ROR","asserted-by":"publisher"}],"name":"National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of 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