Iron promotes both ferroptosis and necroptosis in the early stage of reperfusion in ischemic stroke  

作　　者：Bin Du Zijie Deng Kang Chen Zhangzhong Yang Junfen Wei Liuyao Zhou Jie Meng Ying Cheng Xin Tian Qing-Zhang Tuo Peng Lei 

机构地区：[1]Department of Neurology and State Key Laboratory of Biotherapy,National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [2]Department of Neurology,First Affiliated Hospital of Chongqing Medical University,Chongqing Key Laboratory of Neurology,Chongqing 400016,China

出　　处：《Genes & Diseases》2024年第6期495-509,共15页基因与疾病（英文）

基　　金：upported by the National Key Research and Development Program of China (No.2021YFC2500100);1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University (No.ZYYC23016);the Key Research Projects of Sichuan Province,China (No.24SYSX0093);Major Science&Technology Program of Sichuan Province,China (No.2022ZDZX0021);the National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University (China) (No.Z2023LC005);the Natural Science Foundation of Sichuan Province,China (No.2022NSFSC1509);the Fundamental Research Funds for the Central Universities (China) (No.2023SCU12074).

摘　　要：Programmed cell death contributes to neurological damage in ischemic stroke,especially during the reperfusion stage.Several cell death pathways have been tested preclinically and clinically,including ferroptosis,necroptosis,and apoptosis.However,the sequence and complex interplay between cell death pathways during ischemia/reperfusion remains under investigation.Here,we unbiasedly investigated cell death pathways during ischemia/reperfusion by utilizing RNA sequencing analysis and immunoblot assays and revealed that ferroptosis and necroptosis occurred early post-reperfusion,followed by apoptosis.Ferroptosis inhibitor Liproxstatin-1 effectively inhibited necroptosis during reperfusion,while the necroptosis inhibitor Necrostatin-1 suppressed protein expression consistent with ferroptosis activation.Protein–protein interaction analysis and iron chelation therapy by deferoxamine mesylate indicate that iron is capable of promoting both ferroptosis and necroptosis in middle cerebral artery occlusion/repression modeled mice.Treatment of cells with iron led to a disruption in redox balance with activated necroptosis and increased susceptibility to ferroptosis.Collectively,these data uncovered a complex interplay between ferroptosis and necroptosis during ischemic stroke and indicated that multiple programmed cell death pathways may be targeted co-currently.

关 键 词：DEFEROXAMINE Ferroptosis IRON Ischemic stroke NECROPTOSIS 

分 类 号：R743.3[医药卫生—神经病学与精神病学]