The recent paper by Wang and colleagues in Cardiovascular Research identifies a novel role for a PIWI-interacting RNA (piRNA), called MCPPIR (myocardial cell proliferation-promoting piRNA), in stimulating cardiomyocyte proliferation and cardiac repair following myocardial infarction. This study shows that small noncoding RNAs can directly regulate heart regeneration, an area with limited therapeutic targets.
Using genetic loss- and gain-of-function approaches in mice, the authors show that MCPPIR deficiency attenuates cardiomyocyte proliferation and impairs neonatal heart regeneration. At the same time, cardiomyocyte-specific overexpression of MCPPIR enhances proliferation, reduces fibrosis, and improves cardiac function after ischemic injury. Mechanistically, MCPPIR interacts with the RNA-binding protein HNRNPH1 to promote oxidative 8-oxoguanine (o8G) modification and the stability of POC1B mRNA, resulting in preserving centrosome integrity and stimulating cell cycle reentry in adult cardiomyocytes. This MCPPIR–HNRNPH1–POC1B axis represents a previously unrecognized post-transcriptional mechanism controlling cardiomyocyte proliferative competence.
Although translation to large animals and humans remains to be established, and the long-term safety of activating cardiomyocyte proliferation through this pathway is not yet known, this work represents an important step forward in the field. In particular, questions remain regarding the durability of the regenerative response and potential effects on cardiomyocyte maturation, electrical stability, and arrhythmia risk. It will also be important to determine whether the MCPPIR–HNRNPH1–POC1B axis operates in the human heart and can be targeted in a clinically meaningful way. Nonetheless, the study provides compelling evidence that oxidative RNA modifications and piRNAs can unlock proliferative programs in adult cardiomyocytes, opening new directions for strategies aimed at enhancing endogenous cardiac repair after ischemic injury.
