REVIEW article
Front. Aging Neurosci.
Sec. Neuroinflammation and Neuropathy
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1588920
This article is part of the Research TopicStroke Research in the Elderly: Addressing Ageism and PrognosticationView all 10 articles
Research progress of deubiquitinating enzymes in cerebral ischemia-reperfusion injury
Provisionally accepted
- Renmin Hospital of Wuhan University, Wuhan, China
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Cerebral ischemia-reperfusion injury (CIRI) is a critical pathological process driving neurological deterioration following ischemic stroke, involving multifaceted mechanisms such as inflammatory cascades, oxidative stress, and programmed cell death (PCD). Deubiquitinases (DUBs), as key regulators of the ubiquitin-proteasome system, dynamically modulate protein stability, signal transduction, and subcellular localization through editing the ubiquitin code, exhibiting dual roles in CIRI—both as drivers of pathogenesis and potential therapeutic targets. This review systematically elucidates the core regulatory mechanisms of DUBs in CIRI: (i) suppression of neuroinflammation via modulation of NLRP6/NF-κB pathways; (ii) mitigation of oxidative stress through the KEAP1-NRF2 axis and mitochondrial quality control; and (iii) neuroprotection by intercepting necroptosis, ferroptosis, and other PCD pathways. We further reveal that CIRI disrupts DUBs functionality through a tripartite mechanism—transcriptional dysregulation, catalytic inactivation, and subcellular mislocalization—transforming DUBs from guardians of homeostasis into mediators of injury. Consequently, DUBs-targeted strategies, including small-molecule inhibitors (e.g., IU1, Vialinin A), genetic editing approaches (e.g., BRCC3 silencing, A20 overexpression), and exosome-based delivery systems (e.g., the KLF3-AS1/miR-206/USP22 axis), demonstrate significant neuroprotective potential. However, challenges persist, such as substrate specificity, ubiquitin chain-type dependency, and barriers to clinical translation. Future research must integrate multi-omics technologies, develop brain-targeted delivery platforms, and explore synergistic effects of DUBs modulation with existing therapies to advance precision medicine in stroke treatment.
Keywords: Cerebral ischemia-reperfusion injury (CIRI), deubiquitinases (DUBs), ischemic stroke, Neuroinflammation, Oxidative Stress, programmed cell death (PCD), ubiquitin-proteasome system, targeted therapy
Received: 06 Mar 2025; Accepted: 08 May 2025.
Copyright: © 2025 Qin, Zhu, Lu, Yi, Zhao, Zhang and Jing. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wenfei Zhang, Renmin Hospital of Wuhan University, Wuhan, China
Cheng Jing, Renmin Hospital of Wuhan University, Wuhan, China
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