Ferroptosis-Centered Mitochondria–ROS Loop Drives PFOS-Induced Renal Dysfunction, from Epidemiological Evidence to Mechanistic Insights with Mice Model

Perfluorooctanesulfonate (PFOS) exhibits systemic toxicity, yet its renal impact and mechanism remains unclear. In 296 matched pairs, serum PFOS, perfluorooctanoic acid (PFOA), and five other polyfluoroalkyl substances (PFAS) were significantly elevated and positively correlated with the risk of reduced estimated glomerular filtration rate (eGFR). In vivo, PFOS caused pathological alterations in mouse renal tissue with inflammatory changes, collagen fibrillar hyperplasia, and decreased renal function. PFOS resulted in damaged mitochondria-mediated oxidative stress and lipid peroxidation, enhanced M1-type macrophage polarization, inhibited M2-type macrophage polarization, and elevated Fe²⁺/Fe³⁺ content and reduced ferroptosis-related mRNA and protein levels. Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed these effects via restoring antioxidants, quenching lipid peroxidation, and shifting macrophages from M1 to M2 through down-regulating the LAT1 subunit cluster of differentiation 98 (CD98). In summary, PFOS may correlate positively with the risk of renal dysfunction in humans, and ferroptosis might form the self-amplifying mitochondrial-reactive oxygen species (ROS) hub that propels PFOS nephrotoxicity and can be pharmacologically unplugged to restore redox balance and quench M1-driven renal inflammation.