The highly conserved PIWI-interacting RNA CRAPIR antagonizes PA2G4-mediated NF110-NF45 disassembly to promote heart regeneration in mice.

Targeting the cardiomyocyte cell cycle is a promising strategy for heart repair following injury. Here, we identify a cardiac-regeneration-associated PIWI-interacting RNA (CRAPIR) as a regulator of cardiomyocyte proliferation. Genetic ablation or antagomir-mediated knockdown of CRAPIR in mice impairs cardiomyocyte proliferation and reduces heart regenerative potential. Conversely, overexpression of CRAPIR promotes cardiomyocyte proliferation, reduces infarct size and improves heart function after myocardial infarction. Mechanistically, CRAPIR promotes cardiomyocyte proliferation by competing with NF110 for binding to the RNA-binding protein PA2G4, thereby preventing the interaction of PA2G4 with the NF110-NF45 heterodimer and reducing NF110 degradation. The ability of CRAPIR to promote proliferation was confirmed in human embryonic stem cell-derived cardiomyocytes. Notably, CRAPIR serum levels are lower in individuals with ischemic heart disease and negatively correlate with levels of N-terminal pro-brain natriuretic peptide. These findings position CRAPIR both as a potential diagnostic marker for cardiac injury and as a therapeutic target for heart regeneration through the PA2G4-NF110-NF45 signaling axis.