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

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 DRG2^fl/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.