Geniposide induces hepatotoxicity via the bile acid-induced activation of NLRP3 inflammasome and regulation of the FXR/PERK/TXNIP pathway

Gardenia jasminoides, as a widely used traditional Chinese medicine, excessive consumption of it may lead to severe liver injury. As the main hepatotoxic component in Gardenia jasminoides, the specific mechanism by which geniposide (GE) causes liver injury remains elusive. In this study, we conducted a systematic investigation of the effects of GE on bile acid (BA) metabolism and related signal transduction and inflammatory pathways in healthy Sprague-Dawley (SD) rats after oral administration of a 13-fold clinical equivalent dose (450 mg/kg) for 5 days. It is noteworthy that GE administration altered the content and composition of BAs and disrupted BA metabolism. At the same time, the expressions of farnesoid X receptor (FXR) and its downstream proteins bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP) are significantly inhibited. In addition, the inhibition of FXR will increase the signal transduction of the protein kinase R-like endoplasmic reticulum kinase (PERK)-thioredoxin-interacting protein (TXNIP)-nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome axis, thereby triggering cysteine protease-1 (caspase-1), leading to the release of inflammatory factors and worsening liver injury. The addition of the FXR agonist obeticholic acid (OCA) effectively reversed the expressions of the above proteins and mRNA, and alleviated the liver injury caused by GE by restoring BAs homeostasis and regulating the inflammatory pathway. Conclusion: GE causes severe liver injury by affecting bile acid metabolism and inflammatory pathways, and the inhibition of FXR is a crucial factor.