The deubiquitinase YOD1 in cardiomyocytes mediates septic cardiomyopathy by deubiquitinating and thus stabilizing the NLRP3 inflammasome

  • Br J Pharmacol. 2026 Jul;183(13):3558-3577. doi: 10.1111/bph.70419.
Zhaozheng Zheng  1  2 ,  Yingjie Liao  1  2 ,  Yucheng Jiang  2 ,  Zhihan Jia  1 ,  Wante Lin  1 ,  Diyun Xu  1 ,  Yanhong Jin  1 ,  Qingqing Zhao  2 ,  Gaojun Wu  1 ,  Bozhi Ye  1  3 ,  Guang Liang  1  2  4
Affiliations
  • 1. Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3. Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
PMID: 41913386 DOI: 10.1111/bph.70419
Abstract

Background and purpose: Septic cardiomyopathy (SCM) is a significant contributor to mortality among septic patients, but effective therapeutic strategies are still lacking. Deubiquitinating Enzymes (DUBs) such as ……. function as crucial regulators of protein ubiquitination and may play a fundamental role in the pathogenesis of heart diseases.

Experimental approach: In two models of SCM induced by lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) in C57BL/6J mice, the differential expression of DUB genes was identified by transcriptome Sequencing. Sepsis models were established through LPS injection or CLP surgery in both cardiomyocyte-specific YOD1 knockout (YOD1CKO) mice and littermate wild-type (Yod1fl/fl) mice. Potential substrates of YOD1 were identified by co-immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry.

Key results: Expression of DUB YOD1 was up-regulated in cardiac tissues of LPS/CLP-induced septic mice. Cardiomyocyte-derived YOD1 deficiency alleviated SCM and protected cardiac function in LPS/CLP-challenged mice. Mechanistically, YOD1 interacted with the inflammasome NLRP3 and then deubiquitinated the K48 ubiquitin chain on the NLRP3 protein by its active site H262, thereby blocking degradation of NLRP3 in cardiomyocytes. Consequently, NLRP3 activation and NLRP3-driven Pyroptosis were increased in both cardiomyocytes and septic mouse hearts. Inhibition of NLRP3 counteracted the protective effects of YOD1 knockout in SCM mice. Furthermore, pharmacological inhibition of YOD1 improved myocardial injury elicited by CLP in mice.

Conclusion and implications: Cardiomyocyte YOD1 mediated SCM by deubiquitinating NLRP3 and promoting NLRP3-driven Pyroptosis. Our results have revealed a new YOD1-NLRP3 axis in cardiomyocytes and identified YOD1 as a novel therapeutic target for treating SCM.

Keywords
NLRP3; YOD1; cardiomyocyte; pyroptosis; septic cardiomyopathy.
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