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We have identified that soluble folate receptor \u03b3 (FOLR3), which is expressed in humans but not in rodents, is a secreted protein that is elevated in the livers of patients with MASH but not in those with metabolic dysfunction\u2013associated steatotic liver disease, those with type II diabetes, or healthy individuals. Global proteomics showed that FOLR3 was the most highly significant MASH-specific protein and was positively correlated with increasing fibrosis stage, consistent with stimulation of activated hepatic stellate cells (HSCs), which are the key fibrogenic cells in the liver. Exposure of HSCs to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistically potentiated by TGF\u03b21. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGF\u03b2 signaling. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human MASH. Our study thus uncovers a role of FOLR3 in enhancing fibrosis.<\/jats:p>","DOI":"10.1126\/scitranslmed.ade2966","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T17:58:48Z","timestamp":1695837528000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Secreted folate receptor \u03b3 drives fibrogenesis in metabolic dysfunction\u2013associated steatohepatitis by amplifying TGF\u03b2 signaling in hepatic stellate cells"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6916-5641","authenticated-orcid":true,"given":"Connor","family":"Quinn","sequence":"first","affiliation":[{"name":"Temple University School of Pharmacy, Philadelphia, PA 19140 USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1356-0416","authenticated-orcid":true,"given":"Mario 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