Cardioprotective Potential of Hedyotis corymbosa in Drug-induced Cardiotoxicity: Insights from Network Pharmacology and Preclinical Studies

INTRODUCTION: Cardiovascular diseases (CVDs) remain a major global health threat, accounting for a significant proportion of deaths worldwide. Doxorubicin (DOX) and Isoproterenol (ISO) are known to induce cardiotoxicity primarily through the generation of reactive oxygen species (ROS). METHODS: Drug-likeness analysis of selected phytochemicals was performed using SwissTargetPrediction and SuperPred 3.0. Genes associated with DOX-induced cardiotoxicity were curated from GeneCards, OMIM (Online Mendelian Inheritance in Man), and DisGeNet. Molecular docking was performed to evaluate potential interactions with TOP2A, HIF1A, ABCB1, NOS3, PIK3R1, SRC, ABL1, and NR3C2. An in vivo cardiotoxicity model using DOX and ISO was employed to assess the cardioprotective effects of ethanolic extracts of Hedyotis corymbosa (EEHC). Wistar rats of either sex, weighing 200-220 g, were used in the study. RESULTS: Docking scores of Corycavidine against hub genes ranged from -6.66 kcal/mol to -1.26 kcal/mol, while MM-GBSA binding energies ranged from -50.22 kcal/mol to -8.28 kcal/mol, with the strongest binding observed for ABL1 (-50.22 kcal/mol). The NBE (cumulative ΔG_Coul and ΔG_vdW) was highest for NOS3 (-87.46 kcal/mol). EEHC administration significantly decreased CKMB, malondialdehyde, and glutathione levels, while HDL, catalase, and superoxide dismutase levels were markedly increased, accompanied by reductions in total blood cholesterol and triglyceride levels. DISCUSSION: DOX and ISO treatment resulted in myocardial wall thickening and lipoprotein accumulation, suggesting cardiac dysfunction. Computational docking and MM-GBSA analyses of 16 hub genes revealed a favorable binding profile of Corycavidine with several key proteins implicated in cardiovascular regulation and injury responses. CONCLUSION: These findings suggest that Corycavidine may serve as a multi-target cardioprotective agent, potentially modulating oxidative stress, inflammation, endothelial function, and cellular survival pathways.