Rewiring cell identity and metabolism to drive cardiomyocyte proliferation

The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes. In contrast, lower vertebrates such as zebrafish retain the ability to fully regenerate heart after injury. This capacity is driven not only by transcriptional and structural plasticity but also by metabolic reprogramming that supports cardiomyocyte proliferation. Adult mammalian cardiomyocytes lack both features, remaining largely refractory to regenerative cues. These limitations have prompted efforts to identify extrinsic genetic and metabolic regulators capable of reactivating proliferative competence in adult cardiomyocytes. In this review, we highlight recent advances in the molecular and metabolic control of cardiomyocyte cell-cycle reentry, focusing on strategies that modulate dedifferentiation, proliferation, and redifferentiation as well as metabolic state transitions. We also examine emerging translational approaches in swine models, which more closely recapitulate human cardiac physiology than rodents. Together, these insights provide a roadmap for unlocking endogenous regenerative pathways and identify key challenges in translating these findings into therapies for heart failure.