A systematic review and preclinical meta-analysis investigating the natural flavonoid naringenin indicates that the compound provides notable cardioprotective effects in animal models of myocardial ischemia-reperfusion injury. Myocardial ischemia-reperfusion injury represents a primary contributor to cardiovascular mortality worldwide. Current medical interventions directed against this form of tissue damage continue to display limited therapeutic efficacy while carrying significant adverse effects, underscoring an urgent clinical need for safer and more effective therapeutic alternatives. Prior preclinical literature had identified naringenin as a candidate compound displaying antioxidant, anti-inflammatory, and anti-apoptotic properties that showed promising cardioprotective potential. Nevertheless, the existing preclinical evidence remained largely fragmented, and no prior systematic quantitative evaluation had evaluated the consistency and magnitude of its protective effects.

To resolve these gaps, the study authors conducted an exhaustive search across five comprehensive bibliographic databases from their inception through January 2025. The electronic search covered PubMed, Embase, Web of Science, the Cochrane Library, and the China National Knowledge Infrastructure, specifically targeting preclinical animal investigations examining naringenin administration in the setting of myocardial ischemia-reperfusion injury. Following systematic screening, a total of 32 distinct animal studies involving 544 experimental animals met all predetermined eligibility criteria and were selected for quantitative synthesis. The methodological quality of all included animal studies was formally evaluated using the SYRCLE risk of bias tool, a standardized instrument designed specifically for preclinical animal experiments.

The meta-analysis established both primary and secondary outcome measures to quantify the physiological, enzymatic, and cellular impacts of naringenin administration. Primary outcome measures were defined as the myocardial infarction area, circulating myocardial enzyme concentrations, and functional hemodynamic indicators of cardiac performance. Secondary outcome measures encompassed cellular apoptosis indices, inflammatory factor concentrations, and biological markers related to oxidative stress. All statistical analyses were executed using R version 4.6.1. The standardized mean difference, adjusted for small sample sizes using Hedges’ g alongside its corresponding 95 percent confidence intervals, served as the primary effect size metric across all comparisons.

To account for anticipated variance among experimental protocols, the investigators evaluated between-study heterogeneity using the I-squared statistic. The statistical framework utilized restricted maximum likelihood as the random-effects estimator, and the Hartung-Knapp correction was applied to guarantee accurate and robust confidence intervals. To assess whether extreme findings from individual experiments distorted the aggregate conclusions, the researchers performed a leave-one-out sensitivity analysis. Subgroup analyses were also carried out to detect and explore specific sources of heterogeneity among the included studies. Publication bias was evaluated qualitatively through funnel plot inspection, with Egger’s test and the non-parametric trim-and-fill method applied when quantitative correction was warranted.

The quantitative meta-analysis revealed that naringenin intervention significantly reduced the myocardial infarction area compared to control conditions, demonstrating a substantial pooled effect size of Hedges’ g equal to -3.75. Myocardial cellular injury markers similarly displayed substantial declines, as naringenin lowered levels of lactate dehydrogenase (LDH) with an effect size of Hedges’ g equal to -6.10, and reduced creatine kinase myocardial band (CK-MB) with an effect size of Hedges’ g equal to -6.79. Left ventricular end-diastolic pressure (LVEDP) was likewise significantly reduced, showing an effect size of Hedges’ g equal to -3.57. In contrast, while creatine kinase (CK) levels showed a general downward trend following naringenin treatment, this particular reduction did not reach statistical significance, yielding a Hedges’ g of -7.77 with a 95 percent confidence interval spanning -15.79 to 0.25 and a P-value of 0.056.

Naringenin administration also led to marked improvements in dynamic measures of ventricular performance (all P < 0.05). Significant enhancements were observed in 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). Although heart rate showed a slight upward trend among treated animals, the change was not statistically significant (Hedges’ g = 1.22, 95% CI [-0.29, 2.74], P = 0.098). At the cellular and molecular levels, naringenin significantly reduced the overall apoptosis index (Hedges’ g = -4.64) and pro-apoptotic Bax protein expression (Hedges’ g = -3.64), while significantly elevating anti-apoptotic Bcl-2 protein expression (Hedges’ g = 6.14). The compound concurrently suppressed key inflammatory mediators, significantly reducing interleukin-1β (IL-1β, Hedges’ g = -4.93) and tumor necrosis factor-α (TNF-α, Hedges’ g = -3.57). Oxidative stress was markedly mitigated, evidenced by significant reductions in malondialdehyde (MDA, Hedges’ g = -5.05) and significant increases in superoxide dismutase (SOD) activity (Hedges’ g = 6.26).

Synthesizing the pooled evidence, the authors concluded that naringenin exhibits clear cardioprotective properties against myocardial ischemia-reperfusion injury in preclinical experimental models. The mechanistic pathway appears to center on the concurrent attenuation of oxidative stress, inflammation, and cellular apoptosis, operating alongside direct improvements in cardiac functional hemodynamics. Nevertheless, the researchers cautioned that the conclusions must be interpreted with care because of inherent methodological limitations in the underlying preclinical studies and the potential presence of publication bias. The authors emphasized that further rigorous preclinical trials and well-designed clinical studies are warranted before the translational therapeutic potential of naringenin can be established in human patients. The systematic review protocol was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols under registration identifier INPLASY202630057.

Subject of Research: Preclinical meta-analysis of naringenin in animal models of myocardial ischemia-reperfusion injury

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

Article References: He, Z., Xie, N., Shao, X., Li, W., Xing, S., Wang, X., Duan, L., Lv, P., Zhao, X., Yu, Z., Feng, J., Li, X., & Fan, K. (2026). Protective effects and underlying mechanisms of naringenin in myocardial ischemia/reperfusion injury: a systematic review and preclinical meta-analysis. Frontiers in Pharmacology, 17, Article 1869715. https://doi.org/10.3389/fphar.2026.1869715

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1869715

Keywords: naringenin, myocardial ischemia-reperfusion injury, cardioprotection, preclinical meta-analysis, infarct size, cardiac function, oxidative stress, flavonoids, Protective, effects, underlying, mechanisms