Bavachinin causes cholestasis by down-regulating BAAT expression and disrupting glycocholic acid synthesis in human liver organoids

Psoraleae Fructus (Bu Gu Zhi, BGZ) is extensively utilized for dermatological and osseous disorders in China. BGZ-induced liver injury has become one of the major concerns, which predominantly cause cholestasis, with the pathogenesis not being fully elucidated. Currently, studies on hepatotoxic mechanisms of BGZ have mainly been conducted on 2D cell culture systems or rodent models, which may not fully encapsulate human pathophysiology. Therefore, we generated human liver organoids (HLOs) from healthy donor(s) for living-related liver transplantation to explore the hepatotoxic mechanism. We identified bavachinin (BVC) as the most hepatotoxic component for cholestasis. After validating by CLF tests, we identified BVC caused cholestasis by down-regulating BAAT, which catalyzes the amidation of bile acids. We also found that up-regulating BAAT with harmaline could mitigate cholestasis and enhance cell viabilities in HLOs. We further demonstrated that glycocholic acid (GCA) levels decreased in BVC-treated HLOs. Supplementation of GCA to BVC-treated HLOs significantly improved cell viabilities. Collectively, our data suggested that BVC impaired the GCA synthesis by down-regulating the expression of BAAT, thereby inducing cholestasis.