Cardiac regeneration and repair: the emerging mechanisms and therapeutic approaches

Myocardial infarction, characterized by irreversible cardiomyocyte loss, progressive cardiac fibrosis and subsequent deteriorated heart function, constitute an intractable global health burden. Promoting endogenous cardiomyocyte proliferation to achieve functional cardiac regeneration represents an available foreground for combatting heart failure. Based on extensive preclinical evidence, researchers have characterized the cellular and molecular mechanisms governing cardiomyocyte proliferation and elucidated the modulatory influence of the metabolic factors and extracellular matrix. Insights from various studies have facilitated the development of regenerative approaches that reprogramming terminally differentiated cardiomyocytes toward a more metabolic plastic and fetal-like state, thereby enhancing the proliferative and reparative potential. Integration of metabolic and mechanical signals has emerged as a critical determinant of successful cardiomyocyte reactivation, providing a mechanistic rationale for combinatorial therapeutic strategies. Nevertheless, despite remarkable progression in mechanistic understanding and proof-of-concept studies, cardiac regeneration protocols advanced to robust clinical validation or pharmacal application have yet to be developed. This review provides a historical and biologically grounded synthesis of preclinical advances in cardiac repair, regeneration and cardiomyocyte reprogramming, with particular emphasis on translational feasibility and clinical applicability. Current strategies and preclinical trial outcomes are summarized to construct a readiness framework that maps the developmental maturity of each approach. Finally, the review highlights existing biological and technical barriers, as well as emerging opportunities poised to shape the future of cardiac regenerative medicine.