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Outline
To investigate the role of poly(rC)-binding protein 1 (PCBP1) in cadmium (Cd)-induced ferroptosis in mouse neuroblastoma Neuro-2a (N2A) cells.
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.
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.
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.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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