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

Abstract

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.

Keywords

Cardiotoxicity / Resveratrol / Curcumin / Doxorubicin / Oxidative stress / Inflammation / Network pharmacology

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