Hexafluoropropylene oxide dimer acid exposure disrupts hepatic lipid metabolism by modulating the RBP4-STRA6 axis

Hexafluoropropylene oxide dimer acid (GenX), an emerging per- and polyfluoroalkyl substance (PFAS) detected in environmental matrices and drinking water sources, raises significant environmental health concerns due to its persistence and potential toxicity. This study investigated the hepatotoxic mechanisms of GenX through multi-omics approaches using in vivo (zebrafish) and in vitro (HepG2 cells) models. Environmentally relevant GenX exposure induced dose-dependent increases of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triacylglycerol (TAG), accompanied by hepatic histopathological damage. Multi-omics analyses revealed that GenX disrupted hepatic lipid homeostasis by activating de novo lipogenesis (DNL) and TAG biosynthesis pathways, with retinol binding protein 4 (RBP4) identified as a critical molecular mediator. Mechanistically, GenX may trigger downstream signaling by enhancing the RBP4-STRA6 interaction, promoting excessive fatty acid synthesis and subsequent hepatic lipid accumulation. Genetic inhibition of RBP4 attenuated GenX-induced lipid deposition. Overall, our findings elucidate a novel RBP4-mediated mechanism underlying GenX-driven hepatotoxicity and provide critical insights into the health implications of PFAS alternatives.