Abstract
Myocardial ischemia-reperfusion (I/R) injury remains a major contributor to infarct expansion and adverse cardiac remodeling despite advances in timely reperfusion therapy. Although restoration of blood flow is essential for myocardial salvage, the abrupt transition from ischemia to reperfusion paradoxically exacerbates cardiomyocyte injury through profound metabolic, ionic, and mitochondrial disturbances. Reperfusion should be viewed not simply as restoration of blood flow, but as a critical biological transition that converts ischemic stress into a self-amplifying injury network. Reperfusion induces excessive reactive oxygen species generation, calcium overload, endothelial barrier disruption, and dysregulated innate immune activation, which converge on mitochondrial dysfunction and diverse forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Emerging evidence highlights that these pathological processes are tightly interconnected through damage-associated molecular pattern signaling, microvascular leakage, and inflammatory amplification, underscoring the limitations of single-target therapeutic approaches. This review summarizes the molecular and cellular mechanisms underlying myocardial I/R injury with a particular focus on oxidative stress, immune modulation, vascular integrity, and ferroptosis. We further discuss current and emerging cardioprotective strategies, including antioxidant therapies, modulation of neutrophil recruitment, microvascular leakage blockade, and anti-ferroptotic interventions. Finally, we address key translational challenges and future perspectives for developing integrated cardioprotective therapies aimed at improving clinical outcomes in acute myocardial infarction.