Multi-omics network toxicology reveals the role of benzo[a]pyrene in ovarian cancer: Integrating gut microbiota dynamics and Mendelian randomization

This study elucidates the role and molecular mechanisms of the environmental carcinogen benzo[a]pyrene (BaP) in the pathogenesis of ovarian cancer by employing an integrative approach that combines multi-omics networks, gut microbiota analysis, and Mendelian randomization. Target genes associated with BaP were identified using ChEMBL, PharmMapper, and GeneCards. Protein-protein interaction networks and functional enrichment analyses were conducted utilizing Cytoscape, while molecular docking (CB-Dock 2) confirmed a strong binding affinity between BaP and core targets (e.g., HSP90AA1: -11.7; AHR: -10.0). Analysis of TCGA data revealed significant dysregulation of 11 core genes in ovarian tumors (e.g., upregulated BCL2L1/CASP3; downregulated ALB/MTOR; all p < 0.001), with prognostic implications (AHR HR = 1.17, p = 0.028; CYCS HR = 1.18, p = 3.5E-05). Single-cell transcriptomic data analysis (via scCancerExplorer) uncovered cell-type-specific enrichment patterns (e.g., AHR/EGF in endothelial/proliferative T cells). Mendelian randomization demonstrated an inverse correlation between serum albumin levels and ovarian cancer risk (HR = 0.43, 95 % CI: 0.27 - 0.70; p = 0.002). Gut microbiota analysis (using gutMGene/SEA databases) identified specific bacteria (Faecalibacterium prausnitzii, Lacticaseibacillus rhamnosus, Fusobacterium nucleatum) that contribute to BaP-induced carcinogenesis via metabolites targeting human genes enriched in cancer pathways. This study establishes a multi-omics network linking BaP exposure to ovarian cancer, emphasizing the interplay between host molecular targets, gut microbiota, and systemic biomarkers (e.g., serum albumin), thereby providing novel insights into the mechanisms of environmental carcinogenesis and potential therapeutic strategies.