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Necroptosis is involved in stroke pathogenesis. However, the molecular mechanisms underlying necroptosis in stroke remain unclear. The mammalian target of rapamycin complex 1 (mTORC1) modulates necroptosis in the gut epithelium. Eukaryotic translation initiation factor 4E (eIF4E)\u2010binding protein\u20101 (4EPB1) is one of the main downstream molecules of mTORC1. This study addresses the role of the 4EBP1\u2013eIF4E pathway in necroptosis. The 4EBP1\u2013eIF4E pathway was found to be activated in both necroptotic HT\u201022 and mouse middle cerebral artery occlusion (MCAO) models. Functionally, 4EBP1 overexpression, eIF4E knockdown, and eIF4E inhibition suppressed necroptosis, respectively. Furthermore, a positive feedback circuit was observed between the 4EBP1\u2013eIF4E and receptor\u2010interacting protein\u20103 (RIP3)\u2013mixed lineage kinase domain\u2010like protein (MLKL) pathways, in which RIP3\u2013MLKL activates the 4EBP1\u2013eIF4E pathway by degrading 4EBP1 and activating eIF4E. This in turn enhanced RIP3\u2013MLKL pathway activation. The eIF4E activation derived from this loop may stimulate cytokine production, which is a key factor associated with necroptosis. Finally, using a mouse MCAO model, the application of eIF4E, RIP3, and MLKL inhibitors was found to have a regulatory mechanism similar to that in the in vitro study, reducing the infarct volume and improving neurological function in MCAO mice.<\/jats:p>","DOI":"10.1002\/mco2.70107","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:49:31Z","timestamp":1739947771000},"source":"Crossref","is-referenced-by-count":16,"title":["Noncanonical feedback loop between \u201cRIP3\u2013MLKL\u201d and \u201c4EBP1\u2013eIF4E\u201d promotes neuronal necroptosis"],"prefix":"10.1002","volume":"6","author":[{"given":"Shuchao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology The Second Xiangya Hospital of Central South University Changsha Hunan China"},{"name":"Center for Medical Research The Second Xiangya Hospital of Central South University Changsha Hunan China"},{"name":"National Clinical Research Center for Mental Disorders 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