Butylated hydroxytoluene ameliorates lead acetate-induced vasculopathy: A mechanistic insight from wistar rat experimental model and computational analysis

Lead (Pb) exposure remains an important public health problem, especially in developing countries, as it has had very harmful vasculotoxic effects. In the present study, BHT, a phenolic antioxidant, is investigated as a protective agent against PbAc-induced vasculopathy through in vivo and in silico methods. Forty-two male Wistar rats were divided into seven groups and were administered BHT (25 or 50 mg/kg b.wt.), PbAc (50 mg/kg b.wt) and a combination of them for 21 days. PbAc intoxication induced major adverse changes in lipid profile, elevated atherogenic index, oxidative stress, inflammatory markers, dysregulated vascular regulators, such as endothelin-1, and nitric oxide. Remarkably, treatment with BHT mitigated dyslipidaemia, replenished the level of antioxidant enzymes (SOD, CAT, GPx, and GSH), and decreased lipid peroxidation. BHT improved protection against the vascular thickening and degeneration induced by PbAc in the aorta, as observed after histological analysis. More so, in silico network pharmacology identified 242 overlapping gene targets between PbAc toxicity and BHT action. Protein-protein interaction and topological comparison of the genes revealed that the JUN, IL-6, AKT1, STAT3 and TNF-α were the central mediators. GO and KEGG enrichment analysis indicated participation in oxidative stress pathways, inflammatory, vascular tone regulation and atherosclerosis-related pathways. Molecular docking studies validated the strong binding affinities of BHT to MAPK8, ITGB1, STAT3, and other hub proteins, suggesting that direct molecular interactions underpin its vasculoprotective effect. Conclusively, BHT reduces PbAc-induced vasculopathy by regulating oxidative stress, inflammatory response and lipid metabolism; a multi-target engagement has been shown by in silico studies.