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Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke

Fuqi Mei1,2, Deyu Deng1,2, Zijun Cao1,2

  • 1School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.

EMBO Molecular Medicine
|February 28, 2025
PubMed

Insights

Deleting Otubain-2 (OTUB2) reduces brain damage and neuronal death after ischemic stroke. OTUB2 inhibition offers a potential new therapy for stroke by blocking necroptosis.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Ischemic stroke is a leading cause of death and disability worldwide.
  • Mechanisms of neuronal death following ischemic stroke are not fully understood.
  • Neuronal death contributes significantly to stroke-induced brain damage.

Purpose of the Study:

  • To investigate the role of Otubain-2 (OTUB2) in ischemic stroke.
  • To elucidate the molecular mechanisms by which OTUB2 influences neuronal death.
  • To evaluate OTUB2 inhibition as a potential therapeutic strategy for ischemic stroke.

Main Methods:

  • Utilized mouse models of ischemic stroke.
  • Assessed neurological deficits, cerebral infarction, neuronal loss, glial activation, and neuroinflammation.
  • Investigated the interaction between OTUB2 and receptor-interacting protein kinase 3 (RIPK3).
  • Examined the effect of OTUB2 deletion and pharmacological inhibition on neuronal necroptosis.
  • Used human brain organoids to study oxygen-glucose deprivation-induced neuronal death.

Main Results:

  • OTUB2 deletion significantly reduced cerebral infarction and neurological deficits in mice.
  • OTUB2 deficiency decreased neuronal loss, glial activation, and neuroinflammation post-stroke.
  • OTUB2 promotes neuronal necroptosis by stabilizing RIPK3 protein levels via deubiquitination.
  • Pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and neuronal death in human brain organoids.

Conclusions:

  • OTUB2 critically regulates neuronal necroptosis and exacerbates ischemic stroke injury.
  • OTUB2 inhibition represents a promising therapeutic avenue for treating ischemic stroke.
  • Targeting OTUB2 may offer a novel strategy to mitigate brain damage after stroke.
Keywords:
Ischemic StrokeNecroptosisOTUB2RIPK3Ubiquitination

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