{"doi":"10.1126/scitranslmed.adk8446","title":"Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose","abstract":"Activation of extracellular matrix–producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)–, carbon tetrachloride (CCl 4 )–, or bile duct ligation (BDL)–induced 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 RARα. 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.","journal":"Science Translational Medicine","year":2024,"id":430819,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1234179,"name":"Jong‐Won Kim","orcid":"0009-0008-1219-6967","position":1,"is_corresponding":false},{"id":1134128,"name":"Junjie Zhu","orcid":"0000-0001-5702-8213","position":2,"is_corresponding":false},{"id":1234180,"name":"Sihan Li","orcid":"0009-0005-6211-6847","position":3,"is_corresponding":false},{"id":1234181,"name":"Jiong Yan","orcid":"0000-0002-3010-8982","position":4,"is_corresponding":false},{"id":905098,"name":"Qing Liu","orcid":"0009-0000-9123-0538","position":5,"is_corresponding":false},{"id":239562,"name":"Imhoi Koo","orcid":"0000-0002-5816-0627","position":6,"is_corresponding":false},{"id":1234182,"name":"С. 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