Synergistic effect of resveratrol and curcumin against doxorubicin-induced cardiac injury: Network pharmacology, molecular mechanisms and in-vivo evidence

Objective: To evaluate the cardioprotective effects of resveratrol and curcumin, individually and in combination, against doxorubicin- induced cardiac toxicity and explore the underlying mechanisms via network pharmacology. Methods: In silico target prediction, enrichment analyses, and Cytoscape network modeling were performed to investigate shared molecular targets and pathways among resveratrol, curcumin and doxorubicin. Male Wistar rats ( n =6/group) received oral treatments of vehicle, nebivolol (5 mg/kg), resveratrol (20 mg/kg), curcumin (100 mg/kg), resveratrol plus curcumin for 28 d, with cardiotoxicity induced via doxorubicin (2.5 mg/kg, i.p .) on days 7 and 14. Cardioprotection was evaluated using electrocardiographic, hemodynamic, biochemical, RT-PCR, and histopathological assays. Results: Network analysis revealed four common targets (NFE2L2/ Nrf2, TNF, CYP3A4, and MAPT) with significant protein-protein interaction enrichment ( P =0.019 6), implicating modulation of redox balance, inflammation, and xenobiotic metabolism. Concomitant therapy with resveratrol and curcumin significantly mitigated doxorubicin-induced cardiac injury by suppressing relative heart weight, reducing myocardial infarction area, reversing electrocardiographic and conduction abnormalities, attenuating dyslipidemia, and lowering serum CK-MB, LDH, and troponin I leakage ( P < 0.05). Furthermore, combination treatment was more effective in restoring cardiac antioxidants, decreasing lipid peroxidation, downregulating mRNA expressions of TNF-α and NF-κB , upregulating Nrf2 mRNA expression, and improving myocardial architecture compared with individual monotherapies. Conclusions: Concomitant therapy with resveratrol and curcumin confers robust cardioprotection against doxorubicin-induced cardiotoxicity in rats, likely via coordinated activation of Nrf2- mediated antioxidant defenses and suppression of TNF-α/NF- κB-driven inflammation, supporting their potential for future investigation as adjunct therapies during anthracycline treatment.