Cardioprotective effects of natural phytochemicals from traditional medicinal plants against doxorubicin-induced cardiotoxicity: A meta-analysis of preclinical studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Natural phytochemicals (NPs) derived from traditional medicinal plants, such as flavonoids from Glycyrrhiza uralensis, terpenoids from Salvia miltiorrhiza, and saponins from Panax ginseng, have been extensively used in ethnopharmacological practices across Asia for treating cardiovascular disorders. These include symptom complexes such as "xiongbi" (chest discomfort) and "xinji" (palpitations), which are analogous to modern doxorubicin-induced cardiotoxicity (DIC). Despite their historical use, the cardioprotective efficacy of these NPs against DIC and their alignment with traditional therapeutic principles remain unquantified. AIM OF THE STUDY: This study aims to provide quantitative evidence for the cardioprotective effects of NPs in preclinical DIC models, and to establish a mechanistic framework that bridges traditional uses with modern pharmacological understanding, thereby informing evidence-based integration of these ethnomedicinal agents into cardio-oncology practice. MATERIALS AND METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines, with protocol registered in PROSPERO (CRD420251050072). Four databases (PubMed, Web of Science, EMBASE, Cochrane Library) were searched for preclinical studies evaluating natural phytochemicals (NPs) in animal models of DIC. Effect sizes for cardiac function, myocardial injury, and oxidative stress were pooled using either fixed-effect or random-effects models based on heterogeneity (I2). Subgroup analyses were stratified by NPs class, mechanisms, and experimental conditions. Methodological quality was assessed using the SYRCLE tool. RESULTS: A total of 33 preclinical studies comprising 656 rodents were included. NPs co-treatment significantly improved cardiac function (LVEF: SMD = 3.95, 95% CI [3.20, 4.70], P < 0.00001; LVFS: SMD = 3.73, 95% CI [2.95, 4.50], P < 0.00001) and reduced myocardial injury (CK-MB: SMD = -4.03, 95% CI [-4.88, -3.18], P < 0.00001; LDH: SMD = -3.39, 95% CI [-4.08, -2.71], P < 0.00001) compared to doxorubicin alone. This cardioprotection was accompanied by enhanced antioxidant defenses (SOD: SMD = 3.98, 95% CI [3.31, 4.66], P = 0.001; MDA: SMD = -3.78, 95% CI [-4.62, -2.95], P < 0.00001). Subgroup analyses revealed differential effects: flavonoids and phenolic acids primarily targeted redox imbalance and ferroptosis-related pathways; terpenoids and alkaloids were associated with preserved mitochondrial function; saponins and polyphenols showed antioxidant and anti-apoptotic effects. A limited number of studies further suggested that some NPs may exert preliminary cardio-oncological dual potential by conferring cardioprotection without compromising antitumor activity. CONCLUSION: This meta-analysis provides quantitative evidence that NPs confer robust, multi-target cardioprotection against DIC through coordinated modulation of oxidative stress, mitochondrial dysfunction, and regulated cell death. The mechanistic heterogeneity supports a stage-oriented and mechanism-informed classification strategy, offering a rational framework for integrating NPs into precision cardio-oncology.