Firre promotes myocardial proliferation and repair via binding to PTBP1 and activating the Akt pathway

The neonatal mammalian heart retains transient regenerative capacity that diminishes shortly after birth. Reactivation of cardiomyocyte proliferation 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 proliferation, 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 proliferation and reducing fibrotic scar area following myocardial injury. Remarkably, Firre administration improved cardiac function, attenuated infarct size, and stimulated cardiomyocyte proliferation in adult mice post-myocardial infarction. Mechanistically, RNA immunoprecipitation revealed direct interaction between Firre and Polypyrimidine Tract Binding Protein 1 (PTBP1). Transcriptome profiling demonstrated Firre-mediated activation of the PI3K/AKT signaling pathway. Furthermore, we identified Phlda3 (Pleckstrin Homology-like Domain Family A Member 3) as a downstream effector, through which Firre facilitates cardiac regeneration by modulating SFPQ-NONO heteromer stability and enhancing DNA repair capacity. These findings establish Firre as a potential therapeutic target for augmenting myocardial repair and regeneration.