Oxidative Stress and Its Impact on Reperfused Myocardium: Pathophysiological Insights and Therapeutic Perspectives

Myocardial ischemia–reperfusion injury (MIRI) represents a major contributor to morbidity and mortality in patients undergoing reperfusion therapy after acute myocardial infarction. Although timely restoration of coronary blood flow is essential for myocardial salvage, reperfusion paradoxically initiates a complex cascade of molecular and cellular events that may aggravate myocardial injury. Oxidative stress is considered one of the central mechanisms underlying MIRI, primarily through excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to mitochondrial dysfunction, calcium overload, endothelial injury, inflammatory activation, and cardiomyocyte death. This review summarizes the current understanding of the pathophysiological mechanisms involved in oxidative stress-mediated reperfusion injury, with emphasis on mitochondrial permeability transition pore opening, inflammasome activation, cytokine release, neutrophil extracellular trap formation, macrophage polarization, and interconnected cell death pathways including PANoptosis. Emerging evidence regarding immunometabolic regulation and epigenetic modulation in MIRI is also discussed. In addition, current pharmacological and non-pharmacological cardioprotective strategies targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling are reviewed, highlighting both promising experimental findings and the persistent challenges in clinical translation. A deeper understanding of the molecular interplay between oxidative stress and inflammatory pathways may facilitate the development of integrated therapeutic approaches aimed at improving myocardial recovery and long-term cardiovascular outcomes following reperfusion therapy.