ALDOC promotes cardiomyocyte proliferation and heart regeneration via suppressing RBM39-ubiquitination
TL;DR
AlDOC is a critical regulator of heart regeneration through the RBM39/PI3K/AKT pathway, and targeted activation of ALDOC or RBM39 represents a potential therapeutic strategy for myocardial injury.
Abstract
The adult mammalian heart exhibits a severely limited regenerative capacity, making myocardial injury a major clinical challenge. Enhancing cardiomyocyte proliferation has emerged as a promising strategy for cardiac repair and regeneration. In this study, we identify aldolase C (ALDOC), a key glycolytic enzyme, whose expression progressively declines during postnatal heart development but is reactivated following neonatal myocardial injury. Cardiomyocyte-specific knockdown of ALDOC impairs cardiomyocyte proliferation and inhibits heart regeneration in neonatal mice after apical resection. Conversely, AAV9-mediated ALDOC overexpression markedly enhances cardiac regeneration and functional recovery in adult mice following myocardial infarction. Mechanistically, ALDOC interacts with RNA-binding motif protein 39 (RBM39) and inhibits TRIM25-mediated ubiquitination and degradation of RBM39, thereby activating PI3K/AKT signaling and promoting cardiomyocyte proliferation. In conclusion, ALDOC is a critical regulator of heart regeneration through the RBM39/PI3K/AKT pathway, and targeted activation of ALDOC or RBM39 represents a potential therapeutic strategy for myocardial injury.