Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke

作者全名："Wei, Chao; Xiao, Zhongnan; Zhang, Yanling; Luo, Zhaoli; Liu, Dongyang; Hu, Liye; Shen, Danmin; Liu, Meng; Shi, Lei; Wang, Xiaotong; Lan, Ting; Dai, Qingqing; Liu, Jing; Chen, Wen; Zhang, Yurui; Sun, Qingyu; Wu, Weihua; Wang, Peipei; Zhang, Chenguang; Hu, Junchi; Wang, Chu; Yang, Fei; Li, Qian"

作者地址："[Wei, Chao; Liu, Meng; Wang, Xiaotong; Liu, Jing; Chen, Wen; Zhang, Yurui; Sun, Qingyu; Wang, Peipei; Yang, Fei] Capital Med Univ, Sch Basic Med Sci, Dept Neurobiol, Beijing 100069, Peoples R China; [Xiao, Zhongnan; Luo, Zhaoli; Hu, Liye; Shen, Danmin; Shi, Lei; Lan, Ting; Wu, Weihua; Zhang, Chenguang; Li, Qian] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100069, Peoples R China; [Zhang, Yanling; Wang, Chu] Peking Univ, Acad Adv Interdisciplinary Studies, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China; [Zhang, Yanling] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China; [Zhang, Yanling] Peking Union Med Coll, Beijing 100050, Peoples R China; [Liu, Dongyang; Wang, Chu] Peking Univ, Coll Chem & Mol Engn, Synthet & Funct Biomol Ctr, Beijing Natl Lab Mol Sci,Key Lab Bioorgan Chem & M, Beijing 100871, Peoples R China; [Dai, Qingqing] Tsinghua Univ, Beijing Tsinghua Changgung Hosp, Sch Clin Med, Dept Geriatr, Beijing 102218, Peoples R China; [Hu, Junchi] Chongqing Med Univ, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400010, Peoples R China; [Yang, Fei] Capital Med Univ, Lab Clin Med, Beijing Key Lab Neural Regenerat & Repair, Beijing 100069, Peoples R China; [Li, Qian] Capital Med Univ, Beijing Key Lab Canc Invas & Metastasis Res, Beijing Key Lab Neural Regenerat & Repair, Lab Clin Med, Beijing 100069, Peoples R China"

通信作者："Yang, F (通讯作者)，Capital Med Univ, Sch Basic Med Sci, Dept Neurobiol, Beijing 100069, Peoples R China.; Li, Q (通讯作者)，Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100069, Peoples R China.; Wang, C (通讯作者)，Peking Univ, Acad Adv Interdisciplinary Studies, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China.; Wang, C (通讯作者)，Peking Univ, Coll Chem & Mol Engn, Synthet & Funct Biomol Ctr, Beijing Natl Lab Mol Sci,Key Lab Bioorgan Chem & M, Beijing 100871, Peoples R China.; Yang, F (通讯作者)，Capital Med Univ, Lab Clin Med, Beijing Key Lab Neural Regenerat & Repair, Beijing 100069, Peoples R China.; Li, Q (通讯作者)，Capital Med Univ, Beijing Key Lab Canc Invas & Metastasis Res, Beijing Key Lab Neural Regenerat & Repair, Lab Clin Med, Beijing 100069, Peoples R China."

来源：CELL DEATH AND DIFFERENTIATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001216059500001

JCR分区：Q1

影响因子：12.4

年份：2024

卷号：31

期号：8

开始页：983

结束页：998

文献类型：Article

关键词：　

摘要："Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH."

基金机构：National Natural Science Foundation of China (National Science Foundation of China); Computing Platform of the Center for Life Science at Peking University

基金资助正文："The purified GPx4U46C mutant protein is generously gifted from Dr. Luhua Lai (Peking University). We thank for suggestions from Dr. Zufeng Guo (Chongqing Medical University) and Dr. Li Su (Peking University Health Science Center). We thank the Computing Platform of the Center for Life Science at Peking University for supporting the LC-MS/MS data analysis. We are grateful to Prof. Renxiao Wang's group at the School of Pharmacy, Fudan University, for their technical aid in the virtual screening job described in this work. Graphical abstract has been created with BioRender (https://BioRender.com)."