Non-canonical role of“S6K1–SGK1”pathway in neuronal necroptosis following traumatic brain injuryOA
Traumatic brain injury(TBI)is characterized by high rates of death and disability.Necroptosis is reported to be involved in neuronal death after TBI.However,additional molecules and related mechanisms underlying necroptosis,particularly during TBI,remain to be elucidated.mTOR and two of its three substrates(4EBP1 and ULK1)are involved in necroptosis.However,direct evidence linking necroptosis to S6K,another key substrate of mTORC1,has been lacking.In this study,we aimed to investigate the regulated role of“S6K1-glucocorticoid-inducible kinase-1(SGK1)”pathway in neuronal necroptosis after TBI.We first showed that the“S6K1–SGK1”pathway was activated during neuronal necroptosis in TNF-α/Smac mimics/Z-VAD-FMK-induced necroptotic cell model and mouse TBI model.Then,inhibition of the“S6K1–SGK1”pathway could decrease necroptosis by regulating the MLKL activation.Next,a rescue assay indicated that S6K1 may regulate necroptosis through modulating SGK1 expression,while not through binding with SGK1.Finally,S6K1 inhibition alleviated neuronal necroptosis,neuro-inflammation,and functional damage via SGK1 in mice after TBI.Our results showed a non-canonical role of“S6K1–SGK1”pathway in neuronal necroptosis following TBI in mice,which will provide a potential therapeutic target for necroptosis treatment in TBI and other necroptosis-related disorders.
Shuchao Wang;Yating Tan;Minghai Hu;Meijuan Wang;Lu Liang;Xing Luo;Dan Chen;Bing Jiang;Ceshi Chen;Jufang Huang;Kun Xiong
Department of Ophthalmology,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China Center for Medical Research,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China National Clinical Research Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China National Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,ChinaCenter for Medical Research,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China Department of Anatomy and Neurobiology,Xiangya School of Basic Medical Sciences,Central SouthUniversity,Changsha,Hunan 410013,ChinaDepartment of Anatomy and Neurobiology,Xiangya School of Basic Medical Sciences,Central SouthUniversity,Changsha,Hunan 410013,ChinaMedical Imaging Center,Qingdao West Coast New District People’s Hospital,Qingdao,Shandong 266100,ChinaDepartment of Ophthalmology,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China Center for Medical Research,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,ChinaCenter for Medical Research,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,ChinaDepartment of Anatomy and Neurobiology,Xiangya School of Basic Medical Sciences,Central SouthUniversity,Changsha,Hunan 410013,China Hunan Key Laboratory of Ophthalmology,Changsha,Hunan 410011,ChinaHunan Clinical Research Center of Ophthalmic Disease,Changsha,Hunan 410011,China National Clinical Research Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China National Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,ChinaKunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650223,China Academy of Biomedical Engineering,Kunming Medical University,Kunming,Yunnan 650500,China The Third Affiliated Hospital,Kunming Medical University,Kunming,Yunnan 650118,ChinaDepartment of Anatomy and Neurobiology,Xiangya School of Basic Medical Sciences,Central SouthUniversity,Changsha,Hunan 410013,China Hunan Key Laboratory of Ophthalmology,Changsha,Hunan 410011,China Department of Radiology,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China National Clinical Research Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,China National Center for Mental Disorders,The Second Xiangya Hospital of Central South University,Changsha,Hunan 410011,ChinaDepartment of Anatomy and Neurobiology,Xiangya School of Basic Medical Sciences,Central SouthUniversity,Changsha,Hunan 410013,China Hunan Key Laboratory of Ophthalmology,Changsha,Hunan 410011,China
医药卫生
mTORNecroptosisOxidative stressS6K1SGK1Traumatic braininjury
《Genes & Diseases》 2026 (4)
P.706-722,17
supported by the National Natural Science Foundation of China(No.82101126,82572869,82172196,82372507,81371011,81671225)the Natural Science Foundation of Hunan Province,China(No.2024JJ5472,2021JJ40873)the Scientific Research Launch Project fornew employees of the Second Xiangya Hospital of Central South University(China)the Flexible Talent Introduction Program of Central South University(China).
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