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Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)\u2013, carbon tetrachloride (CCl\n            <jats:sub>4<\/jats:sub>\n            )\u2013, or bile duct ligation (BDL)\u2013induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RAR\u03b1. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose\/lactotrehalose may represent therapeutic strategies for liver fibrosis.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adk8446","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T21:20:39Z","timestamp":1727299239000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9854-6831","authenticated-orcid":true,"given":"Hung-Chun","family":"Tung","sequence":"first","affiliation":[{"name":"Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, 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