Protective effects and underlying mechanisms of naringenin in myocardial ischemia/reperfusion injury: a systematic review and preclinical meta-analysis
Abstract
BackgroundMyocardial 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.MethodsWe 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 I2. 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.ResultsA 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).ConclusionThis 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 Registrationhttps://doi.org/10.37766/inplasy2026.3.0057 identifier, INPLASY202630057.
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BibTeX
@article{he2026protective,
title = {{Protective effects and underlying mechanisms of naringenin in myocardial ischemia/reperfusion injury: a systematic review and preclinical meta-analysis}},
author = {Zuoyun He and Na Xie and Xupeng Shao and Wenqiang Li and Shuai Xing and Xiaoyue Wang and Liyun Duan and Peng Lv and Xue Zhao and Zizhou Yu and Jiaying Feng and Xiaomeng Li and Kailiang Fan},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1869715},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1869715},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Protective effects and underlying mechanisms of naringenin in myocardial ischemia/reperfusion injury: a systematic review and preclinical meta-analysis
AU - Zuoyun He
AU - Na Xie
AU - Xupeng Shao
AU - Wenqiang Li
AU - Shuai Xing
AU - Xiaoyue Wang
AU - Liyun Duan
AU - Peng Lv
AU - Xue Zhao
AU - Zizhou Yu
AU - Jiaying Feng
AU - Xiaomeng Li
AU - Kailiang Fan
PY - 2026
DA - 2026/11/04
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1869715
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1869715
AB - BackgroundMyocardial 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.MethodsWe 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 I2. 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.ResultsA 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).ConclusionThis 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 Registrationhttps://doi.org/10.37766/inplasy2026.3.0057 identifier, INPLASY202630057.
SN - 1663-9812
ER -