Glycine Promotes Cardiomyocyte Proliferation and Cardiac Regeneration via the GCN2/AKT Axis
While glucose–lipid metabolic remodeling is a major driver of cardiomyocyte proliferative decline, the role of amino acid metabolism in cardiac generation remains poorly understood. Here, we identify glycine as a previously unrecognized pro-proliferative metabolic regulator in mammalian cardiomyocytes. Notably, exogenous glycine supplementation significantly enhanced cardiomyocyte proliferation in both neonatal and adult models, while also demonstrating enhanced efficacy in promoting cardiac repair following myocardial infarction. Mechanistically, glycine activated PI3K–AKT signaling through the amino acid sensor GCN2 and weakened the GCN2–AKT association, thereby facilitating AKT phosphorylation and enabling cardiomyocyte cell cycle re-entry. To address the pharmacokinetic limitations of free glycine administration, specifically its high peak concentration and suboptimal biodistribution profiles, we developed a cardiac-targeted liposomal nanoformulation (LNP@glycine) that exhibited enhanced myocardial accumulation efficacy, reduced dosing requirements, and further improved therapeutic efficacy. Collectively, our findings reveal glycine as a novel metabolic regulator of heart regeneration and highlight a translatable strategy that integrates amino acid-specific metabolic modulation with precision targeted delivery for ischemic heart disease. Overall design: In primary rat cardiomyocytes, treat with 10 mM glycine or PBS for 24 hours, then perform transcriptome sequencing on total RNA.