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PYRCR alleviates myocardial ischemia/reperfusion injury in mice via inhibiting DRG2-mediated cardiomyocyte pyroptosis

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Circular RNAs (circRNAs) are a distinct class of endogenous RNAs characterized by their covalently closed circular structure. CircRNAs play crucial regulatory roles in various biological processes and pathogenesis. In this study we investigated the role of circRNAs in cardiomyocyte pyroptosis and underlying mechanisms. Ischemia/reperfusion (I/R)-induced myocardial injury was induced in mice by ligation of the left anterior descending coronary artery (LAD). Neonatal mouse cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) assault. By using circRNA microarray, we found that the expression levels of a pyroptosis-related circRNA (designated PYRCR) were markedly decreased in H/R-exposed cardiomyocytes and I/R-injured mouse hearts. Overexpression of PYRCR inhibited cardiomyocyte pyroptosis, attenuated I/R-induced myocardial infarction and ameliorated cardiac function in mice. By RNA pull-down assays coupled with MS analysis followed by molecular validation, we identified developmental regulated GTP-binding protein 2 (DRG2) as the direct downstream target of PYRCR. Cardiac-specific DRG2 knockout mice displayed attenuated pyroptosis and enhanced cardiac function following I/R injury compared to DRG2fl/fl controls. DRG2 directly bound to dynamin-related protein 1 (Drp1), the master regulator of mitochondrial fission, and enhanced its protein stability and expression. Importantly, PYRCR competitively disrupted the DRG2-Drp1 interaction, thereby suppressing DRG2-mediated Drp1 expression and subsequently reducing mitochondrial fission, cardiomyocyte pyroptosis, and myocardial damage. In conclusion, we demonstrate that PYRCR, a novel pyroptosis-related circRNA, protects against I/R-induced myocardial injury through the DRG2-mediated modulation of Drp1 activity, offering promising new therapeutic strategies for preventing cardiac damage mediated by cardiomyocyte pyroptosis.

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Fig. 1: Identification and characterization of cardiac pyroptosis-associated circRNAs.
Fig. 2: PYRCR attenuates pyroptosis in vivo.
Fig. 3: PYRCR inhibits H/R-induced pyroptosis in cardiomyocytes.
Fig. 4: PYRCR interacts with Drg2 and maintains its stability.
Fig. 5: Drg2 regulates pyroptosis in vitro.
Fig. 6: Drg2 regulates pyroptosis in vivo.
Fig. 7: DRG2 binds to Drp1 and promotes its protein stability.
Fig. 8: PYRCR regulates mitochondrial fission and cardiomyocyte pyroptosis by targeting DRG2/Drp1.

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Data availability

All data generated in the present study may be requested from the corresponding author.

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Acknowledgements

We thank Prof. Chen Chen and Prof. Dao-wen Wang from Tongji Hospital, Huazhong University of Science and Technology, for providing samples from patients with heart failure and healthy subjects. The mechanism diagram in the article: “By figdraw.com”.

Funding

This work was supported by the National Natural Science Foundation of China (82370291, 82401019, 82270288), the Open Project Program of State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University (HDHY2024007), Qingdao Science and Technology Benefiting the People Demonstration Project (24-1-8-smjk-7-nsh), Major Basic Research Projects in Shandong Province (ZR2024ZD46), Taishan Scholar Distinguished Expert, China Postdoctoral Science Foundation (2024M761553) and Shandong Provincial Natural Science Foundation (ZR2024QH184).

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Author notes

  1. These authors contributed equally: Xin-zhe Chen, Hong-fei Xu, Xue-mei Zhao, Fu-hai Li

Authors and Affiliations

  1. Department of Pathology, Binzhou Medical University Hospital, Binzhou, 256603, China

    Xin-zhe Chen & Xiang-qian Gao

  2. Department of Cardiovascular Surgery, Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China

    Xin-zhe Chen, Jia-hao Ren, Lu-yu Zhou, Cui-yun Liu, Yu-qin Wang, Su-min Yang & Kun Wang

  3. Department of Forensic Medicine, School of Basic Medical Sciences, Suzhou Medical College of Soochow University; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, China

    Hong-fei Xu

  4. State Key Laboratory of Cardiovascular Disease, Heart Failure center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100037, China

    Xue-mei Zhao & Yu-hui Zhang

  5. Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China

    Fu-hai Li

  6. Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Anatomy, Guilin Medical University, Guilin, 541004, China

    Fang Liu

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Contributions

KW, XQG, YHZ, and FL designed and supervised the experiments. XZC, HFX, XMZ, JHR, FHL and LYZ performed the experiments. CYL, YQW, SMY, XZC and HFX analyzed the data. XQG, KW, YHZ and XZC wrote the manuscript.

Corresponding authors

Correspondence to Fang Liu, Yu-hui Zhang, Kun Wang or Xiang-qian Gao.

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All the animal studies conformed to Directive 2010/63/EU of the European Parliament and were approved by the Biomedical Research Ethics Committee of Qingdao University.

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Chen, Xz., Xu, Hf., Zhao, Xm. et al. PYRCR alleviates myocardial ischemia/reperfusion injury in mice via inhibiting DRG2-mediated cardiomyocyte pyroptosis. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01604-9

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