Summary (2024-01-16) Requires notification to consumers of collection and disclosure of personal data by certain entities. [Approved P.L.2023, c.266.]

Drug abuse exacerbates cholesterol and bile acids burden, causing liver injury. Geniposidic acid targets FXR Ser332 and His447, together with SRC2-3 recruitment and activated FXR nuclear translocation. Geniposidic acid-activated FXR can upregulate CYPs to accelerate bile acids clearance and activate miR-19a-3p to suppress LXR-mediated cholesterol synthesis, which improving cholesterol and bile acids metabolism in drug-induced liver injury. Abstract Drug-induced liver injury (DILI), caused by chemical drugs and traditional Chinese medicine, often leads to severe outcomes like liver failure due to a lack of early detection markers. Farnesoid X receptor (FXR), a key regulator of bile acid (BA) and cholesterol metabolism, is a potential therapeutic target. This study investigates the pathogenesis, markers, and treatment strategies for DILI, focusing on the hepatoprotective effects of geniposidic acid (GPA) from Gardenia jasminoides J. Ellis . Using cellular and animal models of acute and chronic DILI induced by acetaminophen and triptolide, we explored GPA's mechanisms in BA and cholesterol metabolism. Lipidomic and BA analyses revealed that GPA alleviates DILI by enhancing bile acid synthesis and transport via FXR activation. Experiments using AAV-shFXR, Fxr − / − mice and molecular assays demonstrated that GPA targets Ser332 and His447 on FXR ligand-binding domain, promoting FXR nuclear translocation and initiating cytochrome P450 proteins (CYPs) transcriptional activation for BA metabolism. Additionally, miRNA sequencing and RNA-pulldown assays showed that GPA-activated FXR upregulates miR-19a-3p, binding to LXR 3'UTR to inhibit cholesterol production. These findings reveal the GPA-FXR “structure-target” relationship, highlighting a dual mechanism in which GPA promotes CYPs-mediated bile acid metabolism and miR-19a-3p-mediated cholesterol synthesis inhibition, providing a basis for FXR-targeted DILI therapies.