Firre facilitates myocardial repair by inducing cardiomyocyte cell cycle activity through PTBP1 binding and Akt activation.

The neonatal mammalian heart retains a transient regenerative capacity that diminishes shortly after birth. Reactivation of cardiomyocyte cell cycle activity represents a promising strategy for cardiac repair. This study identifies the nuclear-enriched long non-coding RNA FIRRE (Firre) as a critical regulator of cardiac development and regeneration. In vitro, overexpression of Firre significantly enhanced cardiomyocyte cell cycle activation, as evidenced by increased S-phase entry. In vivo, AAV9-mediated cardiac-specific delivery of Firre extended the regenerative window in neonatal mice by promoting cardiomyocyte cell cycle activity and reducing fibrotic scar formation following myocardial injury. Remarkably, Firre administration improved cardiac function, reduced infarct size, and stimulated cardiomyocyte cell cycle activation in adult mice post-myocardial infarction. Mechanistically, RNA immunoprecipitation revealed a direct interaction between Firre and Polypyrimidine Tract Binding Protein 1 (PTBP1). Transcriptomic profiling demonstrated Firre-mediated activation of the PI3K/AKT signaling pathway. Furthermore, Phlda3 (Pleckstrin Homology-like Domain Family A Member 3) was identified as a downstream effector through which Firre promotes cardiac repair by stabilizing the SFPQ-NONO heteromer and enhancing DNA repair capacity. These findings establish Firre as a potential therapeutic target for enhancing myocardial repair and regeneration through cardiomyocyte cell cycle re-entry.