2. Academic Validation
  3. Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke

Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke

  • Cell Death Differ. 2024 May 8. doi: 10.1038/s41418-024-01303-8.
Chao Wei # 1,  Zhongnan Xiao # 2,  Yanling Zhang # 3 4,  Zhaoli Luo # 2,  Dongyang Liu 5,  Liye Hu 2,  Danmin Shen 2,  Meng Liu 1,  Lei Shi 2,  Xiaotong Wang 1,  Ting Lan 2,  Qingqing Dai 6,  Jing Liu 1,  Wen Chen 1,  Yurui Zhang 1,  Qingyu Sun 1,  Weihua Wu 2,  Peipei Wang 1,  Chenguang Zhang 2,  Junchi Hu 7,  Chu Wang 8 9,  Fei Yang 10 11,  Qian Li 12 13
Affiliations

Affiliations

  • 1 Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 3 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 5 Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
  • 6 Department of Geriatrics, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
  • 7 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400010, China.
  • 8 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China. chuwang@pku.edu.cn.
  • 9 Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China. chuwang@pku.edu.cn.
  • 10 Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. feiyang@ccmu.edu.cn.
  • 11 Laboratory for Clinical Medicine, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China. feiyang@ccmu.edu.cn.
  • 12 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. qianli@ccmu.edu.cn.
  • 13 Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing Key Laboratory of Neural Regeneration and Repair, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China. qianli@ccmu.edu.cn.
  • # Contributed equally.
PMID: 38719928 DOI: 10.1038/s41418-024-01303-8
Abstract

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.

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