Ambient particulate matter exposure induces ferroptosis in hippocampal cells through the GSK3B/Nrf2/GPX4 pathway

作者全名："Gui, Jianxiong; Wang, Lingman; Liu, Jie; Luo, Hanyu; Huang, Dishu; Yang, Xiaoyue; Song, Honghong; Han, Ziyao; Meng, Linxue; Ding, Ran; Yang, Jiaxin; Jiang, Li"

作者地址："[Gui, Jianxiong; Wang, Lingman; Liu, Jie; Luo, Hanyu; Huang, Dishu; Yang, Xiaoyue; Song, Honghong; Han, Ziyao; Meng, Linxue; Ding, Ran; Yang, Jiaxin; Jiang, Li] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurol, Chongqing Key Lab Child Neurodev & Cognit Disorder, Chongqing 400014, Peoples R China; [Jiang, Li] Chongqing Med Univ, Childrens Hosp, Dept Neurol, 136 Zhongshan Er Rd, Chongqing 400014, Peoples R China"

通信作者："Jiang, L (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Neurol, 136 Zhongshan Er Rd, Chongqing 400014, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001176815800001

JCR分区：Q1

影响因子：7.4

年份：2024

卷号：213

期号：　

开始页：359

结束页：370

文献类型：Article

关键词：Particulate matter; Ferroptosis; Neurotoxicity; GSK3B/Nrf2/GPX4 pathway; RNA sequencing analysis

摘要："Epidemiological studies have established a robust correlation between exposure to ambient particulate matter (PM) and various neurological disorders, with dysregulation of intracellular redox processes and cell death being key mechanisms involved. Ferroptosis, a cell death form characterized by iron-dependent lipid peroxidation and disruption of antioxidant defenses, may be involved in the neurotoxic effects of PM exposure. However, the relationship between PM-induced neurotoxicity and ferroptosis in nerve cells remains to be elucidated. In this study, we utilized a rat model (exposed to PM at a dose of 10 mg/kg body weight per day for 4 weeks) and an HT22 cell model (exposed to PM at concentrations of 50, 100, and 200 Ing/mL for 24 h) to investigate the potential induction of ferroptosis by PM exposure. Furthermore, RNA sequencing analysis was employed to identify hub genes that potentially contribute to the process of ferroptosis, which was subsequently validated through in vivo and in vitro experiments. The results revealed that PM exposure increased MDA content and Fe2+ levels, and decreased SOD activity and GSH/GSSG ratio in rat hippocampal and HT-22 cells. Through RNA sequencing analysis, bioinformatics analysis, and RT-qPCR experiments, we identified GSK3B as a possible hub gene involved in ferroptosis. Subsequent investigations demonstrated that PM exposure increased GSK3B levels and decreased Nrf2, and GPX4 levels in vivo and in vitro. Furthermore, treatment with LY2090314, a specific inhibitor of GSK3B, was found to mitigate the PM-induced elevation of MDA and ROS and restore SOD activity and GSH/GSSG ratio. The LY2090314 treatment promoted the upregulation of Nrf2 and GPX4 and facilitated the nuclear translocation of Nrf2 in HT-22 cells. Moreover, treatment with LY2090314 resulted in the upregulation of Nrf2 and GPX4, along with the facilitation of nuclear translocation of Nrf2. This study suggested that PM-induced ferroptosis in hippocampal cells may be via the GSK3B/Nrf2/GPX4 pathway."

基金机构：National Natural Science Foundation of China [82301338]; China Post- doctoral Science Foundation [2022M710553]

基金资助正文：This work was jointly supported by the National Natural Science Foundation of China [grant number 82301338] ; and the China Post- doctoral Science Foundation (grant number 2022M710553) .