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PCBP1-mediated regulation of iron homeostasis suppresses ferroptosis against cadmium-induced neurotoxicity in mouse neuroblastoma cells

Year: 2025
Type: article
Abstract: Objective To investigate the role of poly(rC)-binding protein 1 (PCBP1) in cadmium (Cd)-induced ferroptosis in mouse neuroblastoma Neuro-2a (N2A) cells. Methods N2A cells were exposed to a concentration gradient of CdCl₂ (0, 1, 2, 4 μmol/L) for 72 h. Cell viability was assessed by trypan blue staining. Western blotting was employed to detect the expression of ferroptosis-related proteins (GPX4, HMOX1, ACSL4) and PCBP1. Intracellular Fe²⁺ level and lipid peroxidation were detected using FerroOrange and BODIPY581/591 C11 probes, respectively. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was applied to confirm the critical role of ferroptosis in Cd-induced cytotoxicity. Molecular docking was performed to elucidate the interaction between PCBP1 and ferritin, as well as the binding sites of Cd²⁺. PCBP1 overexpression plasmid was further constructed for functional validation. Results Cd exposure suppressed cell viability in N2A cells in a dose-dependent manner (P<0.01), significantly down-regulated GPX4 expression (P<0.05), up-regulated HMOX1 expression (P<0.01), and induced Fe²⁺ overload and lipid peroxidation (P<0.01). Molecular docking revealed that Cd²⁺ directly bound to the KH2 domain of PCBP1 and then co-localized on the outer surface of ferritin heavy chain. Overexpression of PCBP1 markedly reversed Cd-induced Fe²⁺ accumulation, GPX4 down-regulation, lipid peroxidation, and cell death. Conclusion Cd exposure disrupts PCBP1-mediated iron homeostasis via transcriptional suppression and competitive displacement of metal ions, and then synergistically drives Fe²⁺ overload-triggered ferroptosis cascades, ultimately leading to neurotoxicity. Targeting PCBP1-mediated iron homeostasis can effectively mitigate Cd-induced neurotoxicity, and may serve as a novel therapeutic strategy.
DOI: 10.16016/j.2097-0927.202505051
Authors: JIE Sheng, TIAN Rui, QU Yuchen
Language: English
Open Access status: green
OpenAlex ID: W7090895720
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