青岛大学高向前研究团队报道了PYRCR通过抑制DRG2介导的心肌细胞焦亡来减轻小鼠心肌缺血再灌注损伤。该研究于2025年6月30日发表于国际一流学术期刊《中国药理学报》杂志上。

在这项研究中，课题组研究了环状RNA在心肌细胞焦亡中的作用及其潜在机制。结扎左冠状动脉前降支（LAD）诱导小鼠缺血/再灌注（I/R）心肌损伤。新生儿无主心肌细胞遭受缺氧/再氧（H/R）攻击。通过对circRNA微阵列进行主题化，小组发现在H/R暴露的心肌细胞和I/R损伤的无主题心脏中，一种与焦热相关的circRNA （PYRCR）的表达水平显著降低。PYRCR过表达抑制心肌细胞焦亡，减轻I/R诱导的心肌梗死，改善心功能。通过RNA下拉实验、质谱分析和分子验证，课题组人员确定了发育调节的GTP结合蛋白2 （DRG2）是PYRCR的直接下游靶点。与DRG2fl/fl对照相比，心脏特异性DRG2敲除小鼠在I/R损伤后表现出减弱的焦亡和增强的心功能。DRG2直接与线粒体分裂的主要调控因子动力蛋白相关蛋白1 （dynamin-related protein 1, Drp1）结合，增强其蛋白稳定性和表达。重要的是，PYRCR竞争性地破坏DRG2-Drp1相互作用，从而抑制DRG2介导的Drp1表达，随后减少线粒体分裂、心肌细胞焦亡和心肌损伤。总之，研究团队证明了PYRCR，一种新型的与焦亡相关的环状RNA，通过DRG2介导的Drp1活性的调节来保护I/R诱导的心肌损伤，为预防心肌细胞焦亡介导的心脏损伤提供了有希望的新治疗策略。

据介绍，环状RNA （circRNAs）是一类独特的内源性RNA，其特征是共价封闭的环状结构。CircRNAs在各种生物过程和发病机制中起着至关重要的调节作用。

附：英文原文

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

Author: Chen, Xin-zhe, Xu, Hong-fei, Zhao, Xue-mei, Li, Fu-hai, Ren, Jia-hao, Zhou, Lu-yu, Liu, Cui-yun, Wang, Yu-qin, Yang, Su-min, Liu, Fang, Zhang, Yu-hui, Wang, Kun, Gao, Xiang-qian

Issue&Volume: 2025-06-30

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.

DOI: 10.1038/s41401-025-01604-9

Source: https://www.nature.com/articles/s41401-025-01604-9