Protective effects and underlying mechanisms of naringenin in myocardial ischemia/reperfusion injury: a systematic review and preclinical meta-analysis

Резюме

Background Myocardial ischemia/reperfusion injury (MI/RI) is a leading cause of cardiovascular mortality. Current interventions have limited efficacy and significant adverse effects, creating an urgent need for safer alternatives. Naringenin, a natural flavonoid with antioxidant, anti-inflammatory, and anti-apoptotic properties, has shown promising cardioprotective potential in preclinical studies. However, the evidence remains fragmented, and no systematic quantitative evaluation has been performed. Methods We searched five databases (PubMed, Embase, Web of Science, Cochrane Library, CNKI) from inception to January 2025 for preclinical animal studies on naringenin in MI/RI. Primary outcome measures included myocardial infarction area, myocardial enzyme levels, and cardiac function-related indicators. Apoptosis, inflammatory factors, and oxidative stress-related indicators were defined as secondary outcome measures. Statistical analyses were conducted using R version 4.6.1. The standardized mean difference, adjusted for small sample sizes using Hedges’ g, along with the corresponding 95% confidence interval was used as the effect size measure. Heterogeneity among studies was evaluated using I 2 . The analysis used restricted maximum likelihood as the random-effects estimator, and the Hartung-Knapp correction was applied to ensure an accurate confidence interval. The methodological quality of the included studies was assessed using the SYRCLE risk of bias tool for animal studies. A leave-one-out sensitivity analysis was conducted to investigate the impact of studies with extreme effect sizes on the pooled results. Subgroup analyses were conducted to identify heterogeneity sources. Funnel plots were used to qualitatively assess publication bias. Egger’s test, combined with the trim-and-fill method, was further applied for quantitative correction based on qualitative funnel plot inspection when necessary. Results A total of 32 studies involving 544 experimental animals were analyzed. The findings from the meta-analysis indicated that naringenin intervention significantly reduced the area of myocardial infarction (Hedges’ g = −3.75), as well as lowered levels of myocardial enzymes (lactate dehydrogenase, LDH: Hedges’ g = −6.10; creatine kinase myocardial band, CK-MB: Hedges’ g = −6.79) and decreased left ventricular end-diastolic pressure (Hedges’ g = −3.57). Furthermore, naringenin significantly improved various cardiac function indices, including the maximum rate of left ventricular pressure decrease (−LVdP/dtmax: Hedges’ g = 4.45), the maximum rate of left ventricular pressure increase (+LVdP/dtmax: Hedges’ g = 3.31), and left ventricular developed pressure (LVDP: Hedges’ g = 3.80) (all P < 0.05). Although there was a downward trend in CK levels, this difference did not reach statistical significance (Hedges’ g = −7.77, 95% CI [−15.79, 0.25], P = 0.056). Naringenin significantly increased Bcl−2 protein expression (Hedges’ g = 6.14) and superoxide dismutase (SOD) activity (Hedges’ g = 6.26). Additionally, it significantly reduced the apoptosis index (Hedges’ g = −4.64), Bax protein expression (Hedges’ g = −3.64), interleukin−1β (IL−1β) levels (Hedges’ g = −4.93), tumor necrosis factor-α (TNF-α) levels (Hedges’ g = −3.57), and malondialdehyde (MDA) levels (Hedges’ g = −5.05) (all P < 0.05). Although there was an upward trend in heart rate, this difference was not statistically significant (Hedges’ g = 1.22, 95% CI [−0.29, 2.74], P = 0.098). Conclusion This meta-analysis presents robust evidence indicating that naringenin possesses cardioprotective properties against myocardial ischemia/reperfusion injury (MI/RI). The mechanism of action appears to involve the attenuation of oxidative stress, inflammation, and apoptosis, along with improvement of cardiac function. The conclusions drawn from this analysis must be approached with caution due to methodological limitations and potential publication bias. Further rigorous preclinical and clinical trials are warranted to fully establish its translational potential. Systematic Review Registration https://doi.org/10.37766/inplasy2026.3.0057 identifier, INPLASY202630057.