Ubiquitin-specific protease 25 improves myocardial ischemia–reperfusion injury by deubiquitinating NLRP3 and negatively regulating NLRP3 inflammasome activity in cardiomyocytes

Abstract

	•The deubiquitinating enzyme USP25 was down-regulated both in myocardial ischemia/reperfusion injury (MI/RI) myocardium tissues.
	•The deficiency of USP25 worsened exacerbated MI/RI in mice, whereas the overexpression of USP25 in cardiomyocytes mitigated this pathological phenotype.
	•USP25 directly interacts with the NLRP3 protein and deubiquitinates it via K63 linkage at residue K243 through its active site C178, thus affecting NLRP3-ASC interaction and ASC oligomerization to inhibit NLRP3 activation and pyroptosis in cardiomyocytes.

Keywords

cardiomyocyte,myocardial ischemia–reperfusion injury / NLRP3 / pyroptosis / ubiquitin-specific protease 25

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.