Chen Xiaojuan, Du Zeiyu, Shen Huimin, Huang Lianghua, Zhu Yuxin, Li Yanshu
College of Public Health, Shantou University, Shantou, 515063, China.
Department of Toxicology, College of Public Health, Harbin Medical University, Harbin, 150081, China.
Mol Neurobiol. 2025 Jul 19. doi: 10.1007/s12035-025-05204-w.
Atrazine (ATR) is a widely used herbicide known to induce degeneration of nigrostriatal dopaminergic (DA) neurons, leading to a Parkinson's disease (PD)-like syndrome. Ferroptosis, an iron-dependent non-apoptotic cell death, is implicated in various neurodegenerative diseases, though its specific role in PD remains unclear. In this study, 3657 differentially expressed genes associated with PD from the gene expression database were identified, which are enriched in the ferroptosis pathway. Additionally, ATR-induced SD rats and human SH-SY5Y neuroblastoma cells were used to model PD and explore the effects of mTOR on ferroptosis. The results demonstrated that ATR induces ferroptosis, which can be inhibited by pretreatment with Ferrostatin-1. Furthermore, overexpression of mTOR suppressed ATR-induced damage by activating the GPX4 pathway. These findings suggest that mTOR protects against ATR-induced ferroptosis in PD by modulating the GPX4 pathway, highlighting the potential therapeutic value of targeting mTOR and ferroptosis pathways to mitigate ATR-induced neurotoxicity and PD progression.
阿特拉津（ATR）是一种广泛使用的除草剂，已知会导致黑质纹状体多巴胺能（DA）神经元变性，引发类似帕金森病（PD）的综合征。铁死亡是一种铁依赖性非凋亡性细胞死亡，与多种神经退行性疾病有关，但其在PD中的具体作用尚不清楚。在本研究中，从基因表达数据库中鉴定出3657个与PD相关的差异表达基因，这些基因在铁死亡途径中富集。此外，利用ATR诱导的SD大鼠和人SH-SY5Y神经母细胞瘤细胞建立PD模型，探讨mTOR对铁死亡的影响。结果表明，ATR诱导铁死亡，而Ferrostatin-1预处理可抑制铁死亡。此外，mTOR的过表达通过激活GPX4途径抑制ATR诱导的损伤。这些发现表明，mTOR通过调节GPX4途径保护PD中ATR诱导的铁死亡，突出了靶向mTOR和铁死亡途径以减轻ATR诱导的神经毒性和PD进展的潜在治疗价值。
