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: Primary cardiomyocytes, neonatal mice, and adult mouse models of myocardial infarction were employed to investigate the pro-proliferative effects of glycine on cardiomyocytes. Cardiomyocyte proliferation was assessed by immunofluorescence staining of cell-cycle-related markers. Cardiac function was evaluated by echocardiography, and histopathological alterations were examined using Masson's trichrome staining. To overcome the pharmacokinetic limitations of free glycine and enhance therapeutic efficacy, a cardiac-targeted liposomal nanoformulation (LNP@Gly) was developed and applied Results: Exogenous glycine supplementation (700 mg/kg) consistently enhanced cardiomyocyte proliferation across 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.