Network toxicology, molecular docking, and multi-level bioinformatics integration reveal the targets and mechanisms...

This study aims to clarify the potential mechanisms of ischemic stroke (IS) induced by benzo[a]pyrene (BaP) through integrated network toxicology, molecular docking, and multi-level bioinformatics analyses. Targets of Bap were obtained from STITCH and ChEMBL databases, while IS-related targets were sourced from GeneCards, OMIM, and TTD databases. Differential gene expression was analyzed using combined datasets (GSE58294 and GSE22255 from GEO database), and key genes were validated using RT-qPCR on peripheral blood of IS patients. A nomogram was constructed for risk prediction, and molecular docking simulations were conducted for BaP-target interactions. 21 common targets for BaP and IS were identified, and a molecular regulatory network of BaP, targets, and IS was constructed. Functional enrichment revealed involvement in inflammatory and lipid metabolic pathways. MMP9 and PTGS2 were selected as key genes, showing significant upregulation in IS samples (P < 0.001). These genes exhibited moderate diagnostic accuracy, reflected by area under the curve (AUC) values of 0.716 and 0.718, respectively. Immune infiltration analyses showed that key genes were significantly correlated with neutrophils and eosinophils. Molecular docking demonstrated strong interaction between BaP and MMP9 and PTGS2, yielding docking scores of -9.9 kcal/mol and - 10.9 kcal/mol, respectively. The nomogram demonstrated robust predictive performance (AUC = 0.753) and was externally validated using the GSE16561 dataset (AUC = 0.906). BaP may promote IS pathogenesis by modulating MMP9 and PTGS2, affecting inflammatory response, immune infiltration, and lipid metabolism. These findings provide new insights into environmental toxicants in IS and suggest potential biomarkers for IS diagnosis and therapy.