Quercetin-associated cardioprotection in preclinical myocardial ischemia-reperfusion injury: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Prompt reperfusion is the standard treatment for acute myocardial infarction, but it can induce myocardial ischemia-reperfusion injury (MIRI). Quercetin, a plant-derived flavonoid, has been investigated as a potential cardioprotective agent in preclinical MIRI models; however, its effect magnitude, dose-exposure relevance, and mechanistic specificity remain uncertain. This systematic review and meta-analysis evaluated quercetin monotherapy in vivo and ex vivo MIRI models. METHODS: Databases were searched from inception to March 2026 for controlled preclinical studies comparing quercetin monotherapy with vehicle-treated MIRI controls. The primary endpoint was myocardial infarct size. Secondary outcomes included myocardial injury biomarkers, hemodynamic recovery, oxidative-stress markers, and inflammatory cytokines. Random-effects models calculated standardized mean differences (SMDs) or mean differences (MDs). Subgroup, leave-one-out, split-control, risk-of-bias-informed, dose-response meta-regression, and publication-bias analyses were performed where feasible. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261325366). RESULTS: Twenty studies were included. Quercetin was associated with reduced infarct size compared with vehicle controls (SMD = -2.98, 95% confidence interval -4.37 to -1.58; P < 0.00001). A split-control sensitivity analysis showed an attenuated but directionally consistent effect (SMD = -2.22, 95% confidence interval -3.16 to -1.28). Exploratory dose-response meta-regression did not identify a clear linear association between systemic dose and infarct-size effect. Quercetin was associated with an 18.35-percentage-point improvement in left ventricular developed pressure (LVDP) recovery and favorable changes in selected maximal rates of pressure change (±dP/dtmax). It was also associated with reduced myocardial injury biomarkers, decreased malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH), and lower tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Exploratory subgroup analyses suggested attenuated responsiveness in comorbid or metabolically altered models, but this finding was limited and confounded. Egger testing suggested possible small-study effects for infarct size. CONCLUSION: Quercetin is associated with a directionally consistent preclinical cardioprotective signal in rodent in vivo and ex vivo MIRI models. However, the magnitude, mechanistic specificity, and translational relevance remain uncertain because of heterogeneity, possible publication bias, unclear methodological quality, limited pharmacokinetic exposure data, and scarce sex-balanced, comorbid, and large-animal evidence. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261325366, identifier CRD420261325366.