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USP13 ameliorates diabetic cardiomyopathy via deubiquitinating NLRP3 and inhibiting pyroptosis in cardiomyocytes

Cell Death & Differentiation (2025)Cite this article

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Abstract

Diabetic cardiomyopathy (DCM) is a leading cause of diabetes-related mortality. Identifying new functional proteins in DCM pathology and elucidating the underlying mechanisms may provide new therapeutic targets for this disease. Here, we observed that the expression of the deubiquitinating enzyme USP13 was significantly downregulated in DCM mouse heart tissues. We discovered that the expression of USP13 was predominantly localized in cardiomyocytes. Cardiomyocyte-specific knockout of USP13 exacerbated myocardial injury in both type I and type II diabetic mice. Conversely, overexpression of USP13 in cardiomyocytes via recombinant adeno-associated virus 9 (AAV9) showed therapeutic effects against DCM in mice. Interestingly, using co-precipitation and LC-MS/MS analysis, we identified the NOD-like receptor family pyrin domain containing 3 (NLRP3) as a target protein of USP13 in cardiomyocytes. Mechanistically, we have illustrated that USP13 removes the K63-linked ubiquitin chain at K557 of NLRP3 to inhibit NLRP3-ASC interaction, thereby inhibiting ASC polymerization and the activation of NLRP3 inflammasome complex, ultimately alleviating pyroptosis in HG + PA challenged cardiomyocytes. Importantly, we showed that the cardioprotective effects of USP13 overexpression depended on NLRP3, as evidenced by the loss of protection in NLRP3-deficient diabetic mice. Taken together, this study identifies the protective impact and molecular regulation of USP13 in DCM pathology, uncovering a novel cardiomyocyte-specific USP13-NLRP3 axis in DCM.

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Fig. 1: USP13 is downregulated in diabetic hearts.
Fig. 2: USP13 deletion exacerbates type II diabetic cardiomyopathy.
Fig. 3: Cardiomyocyte-specific overexpression of USP13 attenuates diabetic cardiomyopathy in db/db mice.
Fig. 4: USP13 exerts protective effects against cardiomyocyte injury in vitro.
Fig. 5: USP13 interacts with the NACHT domain of NLRP3.
Fig. 6: USP13 alleviates cardiomyocyte injury by inhibiting ASC oligomerization.
Fig. 7: USP13 deubiquitinates NLRP3 through its catalytic site C343.
Fig. 8: USP13 deubiquitinates NLRP3 at lysine 557 to inhibit inflammasome activation.
Fig. 9: USP13 modulates diabetic cardiomyopathy through NLRP3 regulation.

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Data availability

All data needed to evaluate the conclusions in this study are presented in this manuscript or the supplementary information. The materials described in this study are either commercially available or available upon reasonable request from the corresponding authors.

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Acknowledgements

We are grateful to Mengxin Zhang, Lingli Hou, Tongliang Huang, Yanni Dong, and Jiansong Lin from the scientific research center of Wenzhou Medical University for their help in echocardiography and immunofluorescence experiment.

Funding

This study was supported by the National Natural Science Foundation of China (U24A20814 to GL, 82361138563 to YW, and 82270282 to PS) and the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LHDMY23H310001 to PS.

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Authors and Affiliations

  1. Department of Cardiology and the Key Laboratory of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Diyun Xu, Bozhi Ye, Jiaji Chen, Yanhong Jin, Peiren Shan & Guang Liang

  2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Diyun Xu, Jibo Han, Bozhi Ye, Liming Lin, Jiaji Chen, Yanhong Jin, Ying Zhao, Yi Wang & Guang Liang

  3. Department of Cardiology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China

    Jibo Han

  4. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China

    Yi Wang

  5. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Guang Liang

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  1. Diyun Xu
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  2. Jibo Han
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Contributions

GL and SP contributed to the literature search, study design, and manuscript revision. DX, JH, BY, LL, YJ, JC, and YZ, performed the experiments and analyzed the data. YW provided technical help. DX, JH, and BY participated in the drafting of the article. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Peiren Shan or Guang Liang.

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Xu, D., Han, J., Ye, B. et al. USP13 ameliorates diabetic cardiomyopathy via deubiquitinating NLRP3 and inhibiting pyroptosis in cardiomyocytes. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01612-6

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