Bisphenol A (BPA), a widespread environmental endocrine disruptor, is associated with neurodevelopmental disorders and induces oxidative neurotoxicity. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has been implicated in toxicant‑induced neuronal injury. However, whether BPA triggers neuronal ferroptosis through autophagy remains unclear. Using HT‑22 hippocampal neuronal cells as an in vitro model, we investigated the role of autophagy‑dependent ferroptosis in BPA neurotoxicity. BPA exposure caused oxidative damage and mitochondrial ultrastructural abnormalities. It also induced ferroptosis‑related changes, including increased malondialdehyde (MDA), prostaglandin endoperoxide synthase 2 (PTGS2) protein expression, and reactive oxygen species (ROS), as well as decreased glutathione (GSH), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). These effects were reversed by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO). Pharmacological inhibition of autophagy with chloroquine (CQ) also reversed BPA-induced GPX4/SLC7A11 downregulation and PTGS2 upregulation. Notably, BPA decreased the expressions of nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1), which was blocked by CQ. Knockdown of NCOA4 attenuated BPA-induced FTH1 and GPX4 loss, and PTGS2 elevation, indicating that NCOA4-mediated ferritinophagy is required for BPA-induced ferroptosis. Mechanistically, BPA activated AMPK/ULK1 axis while inhibiting mTOR; silencing of AMPK or ULK1 partially abrogated BPA-induced autophagy and ferroptosis. Collectively, these findings demonstrate that BPA activates the AMPK/mTOR/ULK1 signaling pathway to promote NCOA4‑mediated ferritinophagy, leading to ferroptosis in HT‑22 cells. This study provides a novel insight into the molecular mechanisms underlying BPA-associated neurotoxicity.
