Multi-omics investigation of benzo[a]pyrene in gastric cancer: comprehensive network toxicology, machine learning and...

Gastric cancer (GC) risk is shaped by environmental exposures such as benzo[a]pyrene (BaP). Here, we systematically identified BaP-toxicological targets and dissected their contribution to GC development. BaP-related targets were independently predicted with stringent filters from ChEMBL, Similarity Ensemble Approach (SEA) and PharmMapper databases, while GC-related targets were mined from the Comparative Toxicogenomics Database (CTD), GeneCards and OMIM databases. Overlapping targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus GC subtypes, which were subsequently employed 101 machine learning combinations to develop a consensus benzo[a]pyrene-related signature (CBRS) for GC patients. As a result, we identified seven hub toxicological targets: ALB, HSP90AA1, ESR1, INS, TP53, TNF, and EGFR, underscoring their potential central roles in BaP-driven GC pathogenesis. These targets are enriched in the MAPK, Lipid and atherosclerosis, and PI3K-Akt signaling pathway. The BaP-toxicological classifiers and the CBRS prognostic model could provide useful support for risk stratification and inform personalized therapeutic strategies for GC patients. Molecular docking results suggest that BaP exhibits relatively strong binding affinity with these key toxicological targets, potentially implicating their involvement in BaP-induced gastric cancer toxicity. Therefore, this study integrates multi-dimensional omics data with advanced machine learning algorithms to establish a comprehensive analytical framework for the toxicological effects of between BaP and GC, which transcends the limitations of traditional analyses and offers unprecedented insights and evidence chains for elucidating the pathogenesis of GC.