ROS-Mediated Cardiomyocyte Proliferation and Myocardial Regeneration: Mechanisms and Targeted Strategies for Ischemic...

Cardiovascular disease (CVD) persists as the leading cause of global mortality, with adult mammalian hearts exhibiting limited regenerative capacity. Although cardiomyocytes (CMs) can re-enter the cell cycle and undergo DNA synthesis in response to injury, they fail to complete mitosis and cytokinesis, resulting in a functional blockade of productive proliferation following ischemic or aging-related injury. Reactive oxygen species (ROS) exhibit a context-dependent duality in cardiac regeneration: while maintaining redox homeostasis and supporting developmental signaling at physiological concentrations, pathological ROS accumulation exacerbates myocardial decline by inducing DNA damage response (DDR)-mediated cell cycle arrest at G2/M phase, along with structural and functional impairments. This review examines the mechanisms of ROS generation-from its cellular origins to its molecular drivers-in ischemic heart disease, and explores the modulation of regenerative signaling by oxidative stress. We further critically assess emerging therapeutic interventions targeting ROS-mediated myocardial regeneration. By delineating the functional roles of ROS in cardiac injury and repair, this review provides a mechanistic and translational framework for developing redox-based therapies aimed at promoting cardiomyocyte proliferation and myocardial regeneration after ischemic injury.