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Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by \u03b1\u2010naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC\u2010MS\/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and \u03b2\u2010muricholic acid (\u03b2\u2010MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase <jats:italic>Cyp8b1<\/jats:italic>, while enhancing the expression of hepatic efflux transporter <jats:italic>Mrp4<\/jats:italic>, as well as the renal efflux transporters <jats:italic>Mdr1<\/jats:italic> and <jats:italic>Mrp2<\/jats:italic>. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT\u2010induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.<\/jats:p>","DOI":"10.1002\/jat.4562","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T22:31:32Z","timestamp":1700087492000},"page":"582-594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Allocholic acid protects against \u03b1\u2010naphthylisothiocyanate\u2010induced cholestasis in mice by ameliorating disordered bile acid homeostasis"],"prefix":"10.1002","volume":"44","author":[{"given":"Xue","family":"Han","sequence":"first","affiliation":[{"name":"MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering South China University of Technology  Guangzhou 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