PFAS and ferroptosis: molecular mechanisms, organ toxicity, and disease relevance

Abstract Background Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that accumulate in human tissues and may cause prolonged cellular and organ damage. Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, has emerged as a potential mechanism linking PFAS exposure to toxicity. Objective This critical narrative mini-review synthesised original studies directly investigating PFAS-regulated ferroptosis, with emphasis on molecular pathways, affected organs, causal strength, independent replication, disease relevance, and implications for human health risk assessment. Results The final evidence set comprised 18 direct empirical studies. The liver had the most developed mechanistic evidence, but confidence in several detailed perfluorooctane sulfonatehepatocyte pathways was downgraded because multiple reports originated from one research network and lackedindependent replication. Reported mechanisms included glutathione depletion, glutathione peroxidase 4 dysfunction, acyl-CoA synthetase long-chain family member 4-dependent lipid remodelling, nuclear receptor coactivator 4-mediated ferritinophagy, mitochondrial calcium and iron overload, and inter-organelle iron transfer. Ferroptosis-related injury wasalso reported in renal tubular, endothelial, bladder epithelial, oral mucosal, neural, oocyte, and embryonic models.Evidence outside the liver was generally moderate, preliminary, or hypothesis-generating. Perfluorooctanoic acid-mediated suppression of ferroptosis in hepatocellular carcinoma cells further indicated that PFAS effects vary by cellularand disease context. Conclusion Ferroptosis is a credible but context-dependent contributor to PFAS toxicity, but no detailed PFAS–ferroptosis pathway canyet be considered high certainty without stronger external replication. Future studies require verified internal PFAS doses,environmentally relevant mixtures, multiple ferroptosis criteria, orthogonal rescue experiments, organ-relevant models,explicit consideration of sex as a biological variable, and prospective human validation.