YTHDF2 alleviates diabetic cardiomyopathy by targeting m6A-mediated degradation of lncRNA RMRP and inhibiting NLRP3-dependent pyroptosis.

Diabetic cardiomyopathy (DCM) poses a significant threat to diabetic patients, with NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation playing a critical role. In this research, we identified a previously unrecognized molecular pathway that contributed to DCM pathogenesis, mediated by the long non-coding RNA component of mitochondrial RNA processing endoribonuclease (lncRNA RMRP) and the m6A-recognizing protein YTH domain family protein 2 (YTHDF2). Our data demonstrated a marked elevation in lncRNA RMRP expression in both cardiomyocytes exposed to high glucose (HG) and myocardial tissue from DCM mice. Functionally, lncRNA RMRP aggravated pyroptosis, inflammatory injury, and cardiac dysfunction by stabilizing NLRP3 mRNA and enhancing its expression. Mechanistically, YTHDF2 directly bound to lncRNA RMRP, facilitated its m6A modification and promoted its degradation, thereby negatively regulating NLRP3 expression. Crucially, in vivo rescue experiments confirmed that the cardioprotective effects of YTHDF2 overexpression or lncRNA RMRP knockdown were dependent on the suppression of NLRP3. This study revealed a novel YTHDF2/lncRNA RMRP/NLRP3 regulatory axis in DCM, offering new insights for potential therapeutic interventions.