Noncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis

Shuchao Wang; Yun Zhang; Meijuan Wang; Zhihao Zhai; Yating Tan; Weiye Xu; Xiaozhen Ren; Ximin Hu; Jinyou Mo; Jia Liu; Yunfeng Yang; Dan Chen; Bing Jiang; Hualin Huang; Jufang Huang; Kun Xiong

doi:10.1002/mco2.70107

MedComm ›› 2025, Vol. 6 ›› Issue (3) : e70107 DOI: 10.1002/mco2.70107

ORIGINAL ARTICLE

Noncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis

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^,^†

Author information +

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

wangshuchao@csu.edu.cn

drjiangb@csu.edu.cn

huanghualin@csu.edu.cn

huangjufang@csu.edu.cn

xiongkun2001@163.com

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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 / eIF4E / MLKL / necroptosis / RIP3 / stroke

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Shuchao Wang, Yun Zhang, Meijuan Wang, Zhihao Zhai, Yating Tan, Weiye Xu, Xiaozhen Ren, Ximin Hu, Jinyou Mo, Jia Liu, Yunfeng Yang, Dan Chen, Bing Jiang, Hualin Huang, Jufang Huang, Kun Xiong. Noncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis. MedComm, 2025, 6(3): e70107 DOI:10.1002/mco2.70107

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