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We previously demonstrated that inhibiting acid ceramidase (aCDase) increases ceramide in HSCs to ameliorate hepatic fibrosis. Here, we uncover a key signaling pathway that promotes ECM degradation in primary human HSCs, which is dependent upon the activation of protein kinase C\u03b1 (PKC\u03b1) and the induction of matrix metalloproteinase 1 (MMP-1) through extracellular signal\u2013regulated kinase 1\/2 (ERK1\/2). Genetic reduction and pharmacological inhibition with a small molecule reduced aCDase activity, leading to increased collagen degradation and hepatic fibrosis resolution in the carbon tetrachloride (CCl\n            <jats:sub>4<\/jats:sub>\n            ) and fructose, palmitate, cholesterol, and trans-fat (FPC) mouse models. Consistently, ceramide signaling correlated with ECM remodeling and degradation in patients with metabolic dysfunction\u2013associated steatotic liver disease. The findings show that ceramide regulates ECM degradation and establish aCDase as a target for therapeutic regression of fibrosis.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.ads9470","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:58:41Z","timestamp":1756317521000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":23,"title":["Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5161-6946","authenticated-orcid":true,"given":"Sachin","family":"Sharma","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, CA 94143, 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