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MASLD\/MASH is associated with increased senescence proteins, including Activin A, and senolytics have been proposed as a therapeutic approach. To test the role of Activin A, we induced hepatic expression of Activin A in a murine MASLD\/MASH model. Surprisingly, overexpression of hepatic Activin A dramatically mitigated MASLD, reducing liver steatosis and inflammation as well as systemic fat accumulation, while improving insulin sensitivity. Further studies identified a dramatic decrease in the lipid-associated macrophages marker glycoprotein NMB (Gpnmb) by Activin A, and Gpnmb knockdown in the same model produced similar benefits and transcriptional changes to Activin A expression. These studies reveal a surprising protective role for Activin A in MASLD and the potential for SASP proteins to have context-specific beneficial effects. Moreover, they implicate both Activin A and Gpnmb as potential therapeutic targets for this condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.2337\/db23-0357","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T16:03:05Z","timestamp":1699372985000},"page":"260-279","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":23,"title":["Roles of Activin A and Gpnmb in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)"],"prefix":"10.2337","volume":"73","author":[{"given":"Huan","family":"Liu","sequence":"first","affiliation":[{"name":"1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA"},{"name":"2Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, 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Baldovino","family":"Guerra","sequence":"additional","affiliation":[{"name":"1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA"},{"name":"2Institute for Heart and Brain Health, University of Michigan Medical Center, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Stanford University School of Medicine, Stanford, CA"},{"name":"6Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA"},{"name":"7Stanford Cardiovascular Institute, Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin J.","family":"Svensson","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Stanford University School of Medicine, Stanford, CA"},{"name":"6Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA"},{"name":"7Stanford Cardiovascular Institute, Stanford University School of Medicine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bishuang","family":"Cai","sequence":"additional","affiliation":[{"name":"8Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Soukas","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6387-0386","authenticated-orcid":false,"given":"Anthony","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA"},{"name":"2Institute for Heart and 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