2. Academic Validation
  3. Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke

Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke

  • EMBO Mol Med. 2025 Feb 28. doi: 10.1038/s44321-025-00206-6.
Fuqi Mei 1 2,  Deyu Deng 1 2,  Zijun Cao 1 2,  Liyan Lou 1 2,  Kangmin Chen 1 2,  Minjie Hu 2,  Zhenhu Zhu 2,  Jiangyun Shen 2,  Jianzhao Zhang 1 2,  Jie Liang 3,  Jingyong Huang 4,  Min Bao 5,  Ari Waisman 6,  Xu Wang 7 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
  • 2 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China.
  • 3 Department of Rehabilitation, Central Hospital of Jinhua City, 321000, Jinhua, China.
  • 4 Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325015, Wenzhou, China.
  • 5 Oujiang Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 325035, Wenzhou, China.
  • 6 Institute for Molecular Medicine, Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
  • 7 School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China. sunrim@163.com.
  • 8 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), 325000, Wenzhou, China. sunrim@163.com.
PMID: 40021931 DOI: 10.1038/s44321-025-00206-6
Abstract

As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating Enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction in neuronal loss, glial activation, and neuroinflammation. OTUB2 was predominantly expressed in neurons and its deletion decreased receptor-interacting protein kinase 3 (RIPK3)-mediated neuronal Necroptosis. Moreover, OTUB2 increased RIPK3 protein abundance by inhibiting the proteasomal degradation of RIPK3. Mechanistically, OTUB2 removed K48-linked polyubiquitin chains from RIPK3 through its active site C51. Importantly, pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and reduced oxygen-glucose deprivation-induced neuronal death in human brain organoids. These results demonstrate that OTUB2 critically regulates ischemic stroke injury by potentiating neuronal Necroptosis, suggesting that OTUB2 inhibition may become a potential therapeutic approach for treating ischemic stroke.

Keywords

Ischemic Stroke; Necroptosis; OTUB2; RIPK3; Ubiquitination.

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