Glycine promotes cardiomyocyte proliferation and heart regeneration via the GCN2/AKT signaling axis

Rationale: While glucose-lipid metabolic remodeling is recognized as a major contributor to cardiomyocytes proliferation, the role of amino acid metabolism in cardiac regeneration remains poorly understood. In this study, glycine was identified as a previously unrecognized pro-proliferative amino acid. Methods: . Mechanistic studies were performed using RNA sequencing, Western blotting, co-immunoprecipitation (co-IP), immunostaining, pharmacological inhibition and activation approaches. Results: , neonatal, and adult myocardial infarction models. In infarcted adult hearts, glycine supplementation further improved cardiac function and reduced myocardial fibrosis. A cardiac-targeted liposomal formulation of glycine (LNP@Gly) effectively overcame the pharmacokinetic limitations of free glycine and achieved enhanced therapeutic efficacy at a substantially lower dose (4 mg/kg). At the molecular level, glycine treatment was associated with increased AKT phosphorylation, reduced GCN2 activation, and weakened GCN2-AKT interaction. Pharmacological modulation further supported a critical role for the GCN2-AKT axis in glycine-induced cardiomyocyte proliferation and cardiac repair. Conclusions: These findings identify glycine as a novel metabolic regulator of cardiomyocyte proliferation and cardiac regeneration through modulation of the GCN2-AKT signaling axis. Moreover, the integration of amino acid-specific metabolic regulation with cardiac-targeted nanodelivery represents a translatable therapeutic strategy for ischemic heart disease.