Team of Academician Song Weihong Reveals USP25 as a Key Regulatory Molecule in Ischemic Stroke Injury

Team of Academician Song Weihong Reveals USP25 as a Key Regulatory Molecule in Ischemic Stroke Injury

Recently, the research group led by Wang Xu from the team of Academician Song Weihong (Member of the Canadian Academy of Health Sciences and Director of Oujiang Laboratory) published a research paper titled USP25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating TAB2 in the internationally renowned journal Advanced Science (CAS Top Tier 1, IF=15.1). The study found that the deubiquitinating enzyme USP25 alleviates ischemic stroke injury by inhibiting microglia-mediated neuroinflammation, and for the first time discovered that USP25 inhibits inflammatory signal transduction by cleaving K63-specific ubiquitin chains on TAB2. This research clarifies the role and molecular mechanism of USP25 in alleviating ischemic stroke injury, identifying a brand-new intervention target for neuroprotective treatment of ischemic stroke.

Ischemic stroke is a life-threatening cerebrovascular disease with high incidence, disability and mortality rates, accounting for more than 80% of all stroke cases. This study revealed that the deletion of the deubiquitinating enzyme USP25 significantly exacerbated ischemic stroke injury in mice. Functionally, USP25 does not directly affect neuron death caused by oxygen-glucose deprivation; instead, it reduces neuron damage and neurological deficits induced by ischemic stroke by inhibiting microglia-mediated neuroinflammatory responses.

Increased microglial activation in the brains of USP25 knockout mice after ischemic stroke

The study found that compared with normal microglia, the expression of USP25 was upregulated in microglia within the ischemic penumbra of both ischemic stroke patients and mice. This suggests that USP25 is upregulated in a stress-responsive manner after the onset of ischemic stroke to inhibit neuroinflammatory responses.

Upregulated expression of USP25 in microglia of the ischemic penumbra in ischemic stroke patients

In terms of molecular mechanism, this study found that USP25 can cleave K63-specific polyubiquitin chains on TAB2, thereby reducing the activation of the NF-κB and MAPK signaling pathways. Silencing or overexpressing TAB2 in the mouse brain alleviated or exacerbated ischemic stroke injury, respectively; and either silencing or overexpressing USP25 abolished the effect of USP25 deletion on the disease. This research not only identifies a novel target for ischemic stroke treatment but also provides a new regulatory mechanism for inflammatory signal transduction.

Mechanism diagram of this study

This article is cited from Oujiang Laboratory