biostudies-literatureWei CThe Special Research Fund for Central Universities, Peking Union Medical CollegeNational Natural Science Foundation of ChinaBeijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of EducationNational Natural Science Foundation of China (National Science Foundation of China)983-998https://www.ebi.ac.uk/biostudies/studies/S-EPMC11303683biostudies-literatureUnknown31(8)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, itacoCell death and differentiationItaconate protects ferroptotic neurons by alkylating GPx4 post stroke.PMC113036839195310982371321219257019215330182271240320707352220712681971037Shi LLiu JLuo ZLiu MXiao ZWang CWei CShen DLi QYang FLan TWang PSun QHu JZhang YDai QChen WHu LWang XLiu DWu WZhang CfalseItaconate protects ferroptotic neurons by alkylating GPx4 post stroke.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, itaco2024-01-01T00:00:00Z2024 Aug2026-03-18T13:31:39.759Z2025-08-18T09:54:05.131ZS-EPMC113036833871992810.1038/s41418-024-01303-8