Differentiation; Research in Biological Diversity · Oct 28, 2026
Metabolic reprogramming as a central regulator of cardiomyocyte proliferation and heart regeneration
By Kowalik A, Paszenda P, Frątczak A et al.
The adult mammalian heart exhibits a limited capacity for regeneration, primarily due to the post-mitotic state of mature cardiomyocytes. While numerous studies have focused on transcription factors and proliferative signalling pathways, emerging evidence highlights metabolic reprogramming as a fundamental determinant of regenerative competence. During the early neonatal period, cardiomyocytes display a predominantly glycolytic metabolic profile associated with cell cycle activity and regenerative potential. Shortly after birth, a metabolic shift toward mitochondrial oxidative phosphorylation and fatty acid oxidation coincides with cardiomyocyte maturation, increased production of reactive oxygen species, and permanent cell-cycle withdrawal. Recent findings suggest that metabolic remodelling is not merely a consequence of cardiomyocyte differentiation but an active regulator of proliferative capacity. Mitochondrial dynamics, redox balance, and mitophagy critically influence cell cycle re-entry, while metabolites such as acetyl-CoA, NAD+, and α-ketoglutarate (α-KG) modulate epigenetic landscapes that control gene expression programs linked to regeneration. Moreover, metabolic pathways are tightly connected with signalling cascades, including Hippo/YAP, HIF-1α, and mTOR, forming an integrated regulatory network that coordinates energy production with cellular growth and division. In this review, we summarise recent advances in understanding the metabolic control of cardiomyocyte proliferation and discuss emerging therapeutic strategies that modulate metabolic plasticity to enhance heart regeneration. Targeting metabolic pathways may represent a physiologically coherent and potentially safer approach to cardiac repair compared with direct stimulation of cell cycle regulators. Elucidating the molecular mechanisms underlying metabolic reprogramming will be essential for translating regenerative strategies into clinical applications.