Article

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

Xin-zhe Chen1,2, Hong-fei Xu3,4, Xue-mei Zhao5, Fu-hai Li6, Jia-hao Ren2, Lu-yu Zhou2, Cui-yun Liu2, Yu-qin Wang2, Su-min Yang2, Fang Liu7, Yu-hui Zhang5, Kun Wang2, Xiang-qian Gao1
1 Department of Pathology, Binzhou Medical University Hospital, Binzhou 256603, China
2 Department of Cardiovascular Surgery, Institute of Chronic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266021, China
3 Department of Forensic Medicine, School of Basic Medical Sciences, Suzhou Medical College of Soochow University
4 Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, School of Basic Medical Sciences, Soochow University, Suzhou 215123, China
5 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
6 Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266021, China
7 Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, and Department of Anatomy, Guilin Medical University, Guilin 541004, China
Correspondence to: Fang Liu: fang.liu@msn.com, Yu-hui Zhang: zhangyhfw@163.com, Kun Wang: wangk696@qdu.edu.cn, Xiang-qian Gao: xiangqiangao@bzmc.edu.cn,
DOI: 10.1038/s41401-025-01604-9
Received: 4 February 2025
Accepted: 31 May 2025
Advance online: 30 June 2025

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.
Keywords: myocardial infarction; pyroptosis; circular RNAs; PYRCR; DRG2; Drp1

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