Emerging Hexafluoropropylene Oxide Trimer Acid Potently Targets Farnesoid X Receptor and Triggers Hepatic Cholestasis

Abstract Per- and polyfluoroalkyl substance (PFAS) hepatotoxicity is a critical global health threat, and disrupted bile acid metabolism is considered a key driver of PFAS-triggered liver injury, yet the underlying mechanisms remain unclear. Herein, we explored the hepatotoxic mechanisms of emerging hexafluoropropylene oxide trimer acid (HFPO-TA) and dimer acid (HFPO–DA) via farnesoid X receptor (FXR), assessed their health risks, and further compared their effects against perfluorooctanoic acid (PFOA). In rat, HFPO-TA exerted more potent hepatotoxicity than PFOA and HFPO–DA, triggering typical cholestasis through impaired biliary excretion and altered bile acid pool. Mechanistically, all three PFASs promoted the intracellular bile acid accumulation by inhibiting FXR transcriptional activity, with potent HFPO-TA > PFOA > HFPO–DA. Accordingly, HFPO-TA, HFPO–DA, and PFOA can directly bind to FXR though entering the ligand-binding domain via hydrogen bonding and hydrophobic interactions to stabilize an antagonizing conformation. Notably, HFPO-TA bound FXR with 3.25-fold higher affinity than endogenous chenodeoxycholic acid and 50-fold higher affinity than PFOA, accompanied by elevated receptor-bound concentrations (RBCs). RBC-based risk assessment revealed moderate risk in 28.3% of HFPO-TA-exposed residents. Overall, HFPO-TA directly binds to FXR to induce hepatic cholestasis; such FXR-mediated cholestasis poses notable health risks and warrants broad vigilance toward PFAS liver hazards.