Hexafluoropropylene oxide trimer acid (HFPO-TA) exposure predisposes to MASLD through reprogramming hepatic epigenome...

Substitute for perfluorooctanoic acid (PFOA), like hexafluoropropylene oxide trimer acid (HFPO-TA), are sparking growing environmental and health worries because of their persistence and capacity for bioaccumulation. Here, we employed an integrated multi-omics approach to systematically investigate HFPO-TA-induced hepatic lipid metabolic dysregulation in zebrafish. Exposed to a series of concentrations (0, 5, 50, 500 μg/L) of HFPO-TA induced hepatic lipid accumulation and significantly elevated serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Integrated transcriptomic and epigenome analyses revealed that HFPO-TA reprogrammed the hepatic epigenome by selectively activating lipid synthesis-associated enhancers while suppressing lipid oxidation pathways, predisposing to metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, HFPO-TA preferentially remodeled chromatin accessibility and distal enhancers, driving lipogenic gene activation through nuclear receptors, such as peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Finally, functions of PPARα and FXR in HFPO‑TA‑induced lipid imbalance were validated by pharmacological modulators. Overall, our study delivers comprehensive evidence connecting PFOA alternatives to epigenetically driven hepatic steatosis, providing mechanistic understanding to support environmental risk evaluations of emerging perfluoroalkyl and polyfluoroalkyl substances (PFAS) compounds.