Yu Shali, Qin Ziyu, Chen Yuqing, Wang Fengxu, Li Zhijie, Huang Ruiyao, Gao Zhengnan, Qu Yi, Xue Peng, Luo Yonghua, Wang Xiaoke, Zhao Xinyuan
Institute for Applied Research in Public Health, Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
Nantong Fourth People's Hospital, Nantong, China.
Chem Biol Interact. 2025 Mar 1;409:111415. doi: 10.1016/j.cbi.2025.111415. Epub 2025 Feb 13.
Recently, our group identified antimony (Sb) as a novel nerve pollutant, can lead to neuronal injure. However, Sb-associated neurotoxicological mechanisms yet remain unclear. Herein, we found Sb induced hippocampal neuronal ferroptosis in vivo and in vitro. Moreover, ferroptosis inhibition using ferrostatin-1 effectively attenuated Sb-induced neuronal damage in PC12 cells and mice hippocampal regions. Furthermore, iron chelator deferoxamine (DFO) also effectively attenuated ferroptosis and cytotoxicity in PC12 cells. In vitro, Sb treatment reduced expression of the heavy (H)- and light (L)-chain subunits of ferritin (FTH1 and FTL). Moreover, Sb accelerated FTH1 and FTL protein degradation, while ferritin overexpression by plasmid or hippocampal AAV injections dramatically weaken Sb-induced ferroptosis. Sb exposure accelerated autophagic flux, and autophagy inhibition with beclin1 knockdown effectively reduced Sb-mediated ferroptosis. 3-methyladenine treatment in Sb-exposed mice prevented the decrease of FTH1 and FTL protein, resulting in recovery of Sb-induced hippocampal ferroptosis as well as neuronal loss, suggesting that Sb triggered hippocampal neuronal ferritinophagy. Finally, we found Sb upregulated NCOA4 protein expression, while NCOA4 knockdown significantly attenuated Sb-triggered ferroptosis. Collectively, our results proved that Sb triggers hippocampal neuronal ferroptosis through NCOA4-dependent ferritinophagy.
最近，我们团队鉴定出锑（Sb）是一种新型神经污染物，可导致神经元损伤。然而，与锑相关的神经毒理学机制仍不清楚。在此，我们发现锑在体内和体外均可诱导海马神经元铁死亡。此外，使用铁死亡抑制剂Ferrostatin-1可有效减轻锑诱导的PC12细胞和小鼠海马区神经元损伤。此外，铁螯合剂去铁胺（DFO）也可有效减轻PC12细胞中的铁死亡和细胞毒性。在体外，锑处理可降低铁蛋白重链（H）和轻链（L）亚基（FTH1和FTL）的表达。此外，锑加速了FTH1和FTL蛋白的降解，而通过质粒或海马腺相关病毒注射过表达铁蛋白可显著减弱锑诱导的铁死亡。锑暴露加速了自噬通量，用beclin1基因敲低抑制自噬可有效降低锑介导的铁死亡。在暴露于锑的小鼠中用3-甲基腺嘌呤处理可防止FTH1和FTL蛋白减少，从而恢复锑诱导的海马铁死亡以及神经元丢失，这表明锑引发了海马神经元铁蛋白自噬。最后，我们发现锑上调了NCOA4蛋白的表达，而敲低NCOA4可显著减轻锑引发的铁死亡。总的来说，我们的结果证明锑通过NCOA4依赖性铁蛋白自噬触发海马神经元铁死亡。
