Effects of flavonoids on atherosclerosis in ApoE−/− mice: a systematic review and meta-analysis

Background Atherosclerosis (AS) plays a key role in cardiovascular diseases (CVDs) through dysregulated lipid metabolism. Flavonoids have shown promise in combatting AS due to their broad biological impacts. However, a comprehensive assessment of the methodological quality and outcomes of these studies is still lacking. This study con-ducted a rigorous systematic review and meta-analysis of research on the therapeutic potential of flavonoids in ApoE −/− mice, a recognized atherosclerosis model. Methods Relevant literature was sourced from databases like PubMed, Web of Science et al. The studies were assessed for bias using the Cochrane Reviewers Handbook 6.1.0 tool. Data were ana-lyzed for heterogeneity, subgroup analysis, sensitivity analysis, and publication bias using Review Manager 5.4. The meta-analysis synthesized lipid data using standardized mean differences, employed fixed or random effects models based on heterogeneity ( I 2 statistic), and conducted sensitivity and publication bias analyses. Results A systematic search of four databases identified 11 studies meeting the inclusion criteria, all investigating flavonoids in male ApoE −/− mice. A meta-analysis of the extracted data, using random-effects models due to high heterogeneity ( I 2 ≥ 75%), found that flavonoid administration significantly reduced blood levels of LDL-C, TC, and TG while increasing HDL-C. Sensitivity analysis confirmed the robustness of these results, though funnel plots and statistical tests indicated potential publication bias for three of the four lipid markers. All 11 studies also reported a reduction in aortic plaque area, with proposed mechanisms primarily involving antioxidant effects and the inhibition of inflammatory pathways. Conclusion This study synthesizes pre-clinical evidence indicating that flavonoids are promising therapeutic agents for atherosclerosis, primarily through lipid modulation, plaque reduction, and pleiotropic antioxidant/anti-inflammatory mechanisms. The high heterogeneity and potential publication bias highlight the need for more standardized, high-quality animal studies to confirm these effects and better define optimal treatment protocols before clinical translation.