2. Academic Validation
  3. Noncanonical feedback loop between "RIP3-MLKL" and "4EBP1-eIF4E" promotes neuronal necroptosis

Noncanonical feedback loop between "RIP3-MLKL" and "4EBP1-eIF4E" promotes neuronal necroptosis

  • MedComm (2020). 2025 Feb 18;6(3):e70107. doi: 10.1002/mco2.70107.
Shuchao Wang 1 2 3 4,  Yun Zhang 3 4 5 6,  Meijuan Wang 7,  Zhihao Zhai 8,  Yating Tan 2 6,  Weiye Xu 6,  Xiaozhen Ren 6,  Ximin Hu 6,  Jinyou Mo 2,  Jia Liu 2,  Yunfeng Yang 8,  Dan Chen 5 6 9,  Bing Jiang 1 3 4 10,  Hualin Huang 3 4 11,  Jufang Huang 3 4 6 9 12 13,  Kun Xiong 6 9
Affiliations

Affiliations

  • 1 Department of Ophthalmology The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 2 Center for Medical Research The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 3 National Clinical Research Center for Mental Disorders The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 4 National Center for Mental Disorders The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 5 Department of Anesthesiology The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 6 Department of Anatomy and Neurobiology, Xiangya School of Basic Medical Sciences Central South University Changsha Hunan China.
  • 7 Medical Imaging Center Qingdao West Coast New District People's Hospital Qingdao Shandong China.
  • 8 Department of Neurosurgery The Eighth Affiliated Hospital Sun Yat-Sen University Shenzhen China.
  • 9 Hunan Key Laboratory of Ophthalmology Changsha Hunan China.
  • 10 Hunan Clinical Research Center of Ophthalmic Disease Changsha Hunan China.
  • 11 Reproductive Medicine Center, Department of Obstetrics and Gynecology The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 12 Department of Radiology The Second Xiangya Hospital of Central South University Changsha Hunan China.
  • 13 Biobank of the Second Xiangya Hospital of Central South University Changsha Hunan China.
PMID: 39974664 DOI: 10.1002/mco2.70107
Abstract

Stroke is a leading risk factor for disability and death. 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)-binding protein-1 (4EPB1) is one of the main downstream molecules of mTORC1. This study addresses the role of the 4EBP1-eIF4E pathway in Necroptosis. The 4EBP1-eIF4E pathway was found to be activated in both necroptotic HT-22 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-eIF4E and receptor-interacting protein-3 (RIP3)-mixed lineage kinase domain-like protein (MLKL) pathways, in which RIP3-MLKL activates the 4EBP1-eIF4E pathway by degrading 4EBP1 and activating eIF4E. This in turn enhanced RIP3-MLKL 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.

Keywords

4EBP1; MLKL; RIP3; eIF4E; necroptosis; stroke.

Figures
Products