Quercetin in Myocardial Ischemia–Reperfusion Injury: Mechanistic Evidence, Cardioprotective Effects, and Translational Challenges

Myocardial ischemia-reperfusion (I/R) injury remains a major limitation in cardiovascular therapy, where restoration of blood flow paradoxically initiates oxidative stress, inflammation, mitochondrial dysfunction, and cardiomyocyte death. Although multiple pharmacological strategies have been investigated, clinical translation remains limited by inconsistent efficacy and incomplete pathway coverage. Quercetin, a naturally occurring flavonoid with pleiotropic biological activity, has attracted increasing interest as a potential modulator of I/R-associated injury. This systematic review evaluated current evidence regarding the cardioprotective effects and mechanistic actions of quercetin in myocardial I/R injury. A structured literature search identified 25 eligible studies comprising predominantly preclinical in vivo animal investigations, together with limited ex vivo, in vitro, and clinical evidence. Across studies, quercetin consistently reduced infarct size, attenuated myocardial injury biomarkers, and improved cardiac functional parameters. Mechanistically, these effects were associated with suppression of oxidative stress and inflammatory signaling, particularly through modulation of ROS generation, NF-κB activation, PI3K/Akt signaling, mitochondrial dysfunction, and apoptosis-related pathways. Several studies also demonstrated preservation of endogenous antioxidant systems and mitochondrial integrity. However, substantial heterogeneity in experimental design, limited mitochondrial-specific analyses, and the scarcity of comparative clinical studies remain major barriers to translation. Collectively, current evidence supports quercetin as a multi-pathway cardioprotective candidate in myocardial I/R injury, although further standardized and clinically oriented investigations are required to clarify its therapeutic relevance.