PCBP1-mediated regulation of iron homeostasis suppresses ferroptosis against cadmium-induced neurotoxicity in mouse neuroblastoma cells
10.16016/j.2097-0927.202505051
- VernacularTitle:PCBP1调控铁稳态抑制铁死亡对抗镉神经毒性的作用研究
- Author:
Sheng JIE
1
;
Rui TIAN
;
Yuchen QU
;
Li TIAN
;
Jia XIE
;
Mengyan CHEN
;
Mindi HE
;
Zhengping YU
;
Huifeng PI
;
Ping DENG
Author Information
1. 陆军军医大学(第三军医大学)军队劳动卫生学教研室
- Keywords:
cadmium;
poly(rC)-binding protein 1;
ferroptosis;
neurotoxicity
- From:
Journal of Army Medical University
2025;47(19):2315-2326
- CountryChina
- Language:Chinese
-
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 CdCl?(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.
