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Chronic bisphenol exposure is a recognized disruptor of liver function, and although ferroptosis has been implicated, the underlying molecular mechanisms remain poorly defined. Here, integrative chemical proteomics and untargeted metabolomics were used to elucidate mechanisms of ferroptosis induced by bisphenol A (BPA) and bisphenol S (BPS) in hepatic cells. BPA elicited a pronounced ferroptotic phenotype, whereas BPS elicited a moderate phenotype in hepatocytes. Glutathione peroxidase 4 (GPX4) and pyruvate kinase M2 isoform (PKM2) were identified as critical targets, respectively. Validation through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and molecular docking confirmed that BPA specifically binds to GPX4 (KD = 37.6 μM), while BPS exhibits moderate affinity for PKM2 (KD = 14.4 μM). Functional rescue experiments demonstrated that GPX4 overexpression effectively reversed BPA-induced ferroptosis and partially alleviated BPS-induced effects, whereas PKM2 overexpression specifically mitigated BPS-triggered cytotoxicity. Mechanistically, BPA inhibited GPX4 activity, impairing lipid peroxide detoxification and triggering ferroptosis; BPS suppressed PKM2, promoting glucose flux toward the methylglyoxal (MGO) pathway, depleting glutathione, and activating oxidative stress, thereby inducing ferroptosis indirectly. This study clarifies bisphenol-induced ferroptosis via target heterogeneity, providing mechanistic insights that may inform future safety evaluations.
Wang et al. (Thu,) studied this question.