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Activation of extracellular matrix (ECM)-producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of heme-thiolate monooxygenase CYP1B1 was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation as well as pharmacological inhibition of CYP1B1 attenuated HSC activation and protected mice from thioacetamide (TAA)-, carbon tetrachloride (CCl4)-, or bile duct ligation (BDL)-induced liver fibrosis. Metabolomic analysis revealed an increase of the disaccharide trehalose in CYP1B1-deficient HSCs as a result of intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RAR. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent anti-fibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the anti-fibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis mediated by liver-intestine crosstalk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.