Hepatic Bmal1 alleviates cholestasis in female mice through direct regulation of SULT2A1.

Disruption of bile acid (BA) homeostasis and circadian rhythm are interconnected in chronic liver diseases, yet how circadian dysfunction exacerbates cholestasis remains unclear. This study demonstrates that hepatocyte-specific knockout of the core clock gene Bmal1 in female mice markedly aggravates liver injury, inflammation, and fibrosis in an α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis model. The pathological exacerbation is attributed to a profound loss of circadian oscillation and reduced expression of the detoxification enzyme sulfotransferase family 2A member 1 (SULT2A1), resulting in deficient sulfation and hepatic accumulation of cytotoxic bile acids. This hypersusceptibility was further validated in primary hepatocytes under BA overload. Notably, specific in vivo restoration of hepatic SULT2A1 significantly reversed these pathological progressions. Mechanistically, BMAL1 transcriptionally activates Sult2a1 by directly binding to the E-box element within its promoter region. Taken together, our work elucidates the BMAL1-SULT2A1 axis as an essential circadian defense mechanism that maintains hepatic bile acid detoxification homeostasis in female mice, providing a novel theoretical basis for chronotherapeutic strategies in cholestatic liver diseases.