Chronic exposure to Bisphenol AF from gestation through adulthood induces renal injury in 8-month-old mice via lipid metabolism dysregulation and ferroptosis.

Due to its extensive industrial application, bisphenol AF (BPAF) is widely detected in various environmental media and human biological samples, raising significant concerns about its environmental impact and potential adverse health effects. However, its nephrotoxicity remains poorly characterized. In this study, we investigated the nephrotoxic effects of chronic BPAF exposure from gestation through adulthood in mice using a multi-omics approach combining histopathology, transcriptomics, metabolomics, and subsequent in vitro validation. Our results demonstrate that BPAF exposure triggered marked renal fibrosis, disrupted lipid metabolism, and depleted glutathione levels. Integrated multi-omics analysis identified ferroptosis driven by lipid peroxidation as the key pathogenic mechanism. Mechanistically, BPAF activates Trp53, thereby inhibiting the SLC7A11-GPX4 antioxidant axis, and simultaneously upregulates the Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), thereby promoting ferroptosis. Additionally, early activation of the TGF-β/SMAD pathway suggested a pro-fibrotic response secondary to ferroptotic injury. Pharmacological inhibition of ferroptosis by Ferrostatin-1, genetic overexpression of SLC7A11, or knockdown of ACSL4 effectively reversed BPAF-induced lipid peroxidation and fibrotic changes. Collectively, these results demonstrate that chronic BPAF exposure promotes renal fibrosis primarily by disrupting lipid homeostasis and inducing ferroptosis. Our findings highlight BPAF as a potential environmental nephrotoxicant and underscore the need for rigorous safety reassessment of BPA substitutes.