MCPPIR promotes cardiomyocyte proliferation and cardiac repair via o8G oxidation of POC1B mRNA

Abstract Aims The adult mammalian heart possesses severely limited regenerative capacity. Cardiomyocyte loss during cardiac injury, coupled with this restricted regenerative potential, represents a fundamental cause of heart failure and associated mortality. While PIWI-interacting RNAs (piRNAs) are abundantly expressed in cardiac tissue, their functional roles and molecular mechanisms in cardiomyocyte proliferation and heart regeneration remain largely undefined. In this study, we systematically investigated piRNA-mediated regulation of cardiomyocyte proliferation and cardiac repair processes. Methods and results Using piRNA microarray analysis, we identified a novel piRNA regulating cardiomyocyte proliferation, which we named MCPPIR (myocardial cell proliferation-promoting piRNA). Genetic ablation of MCPPIR in mice attenuated cardiomyocyte proliferation and impaired neonatal heart regeneration, while MCPPIR overexpression enhanced proliferation, reduced fibrosis, and improved cardiac function post-myocardial infarction. Through mass spectrometry and RNA pull-down assays, we identified HNRNPH1 as a key binding partner. Cardiomyocyte-specific HNRNPH1 knockout mice displayed enhanced proliferative capacity. o8G-RNA immunoprecipitation sequencing revealed POC1B as the downstream target, with MCPPIR preventing HNRNPH1-mediated repression of POC1B mRNA. Mechanistically, the MCPPIR-HNRNPH1-POC1B axis maintains centrosome integrity, thereby promoting cardiomyocyte proliferation and cardiac repair. Conclusion Our study reveals a previously unrecognized role of piRNAs in regulating cardiomyocyte proliferation. We demonstrate that MCPPIR drives cardiomyocyte proliferation and promotes cardiac repair in adult hearts through o8G-mediated post-transcriptional regulation of POC1B mRNA. These findings establish the MCPPIR/POC1B axis as a promising therapeutic target for ischemic heart diseases, and a novel paradigm for developing regenerative therapies against myocardial injury.