Environmental PFOS and 6:2 Cl-PFESA Reshape Ferroptosis Vulnerability in Liver Cancer.

Ferroptosis, an iron-driven form of programmed cell death characterized by lipid peroxidation and reactive oxygen species (ROS) accumulation, is essential for tissue homeostasis and tumor suppression, yet its regulation in hepatocellular carcinoma (HCC) under environmental pollutant exposure remains unclear. Here, using long-term in vitro and in vivo exposure models with environmentally relevant doses combined with multiomics analyses, we show that per- and polyfluoroalkyl substances (PFAS) exert antithetical effects in HCC and normal hepatocytes. Whereas PFAS promote ferroptosis in normal cells, chronic exposure to perfluorooctanesulfonate (PFOS) and its replacement 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) markedly enhances ferroptosis resistance in HCC. Mechanistically, these contaminants bind to and activate STAT3, which transcriptionally upregulates GPX4, establishing a STAT3-GPX4 self-activating loop that suppresses lipid peroxidation and protects tumor cells from ferroptotic death. Notably, 6:2 Cl-PFESA shows stronger activity than PFOS, challenging its designation as a safer substitute. Our findings reveal a striking cell type-specific duality of PFAS action─inducing ferroptosis in normal hepatocytes but enabling evasion in HCC through signaling reprogramming. This dichotomy advances understanding of pollutant-cancer interactions, highlights the STAT3-GPX4 axis as a therapeutic vulnerability, and underscores the health risks posed by PFAS replacements.