Multi-omics characterization of benzo[a]pyrene toxicity networks identifies SERPINE1 and STK3 as prognostic biomarkers and therapeutic targets in head and neck squamous cell carcinoma.

Benzo[a]pyrene (BaP), a ubiquitous environmental carcinogen predominantly found in tobacco smoke and air pollution, plays a pivotal role in head and neck squamous cell carcinoma (HNSC) pathogenesis. However, the molecular networks governing BaP-induced toxicity and programmed cell death (PCD) mechanisms in HNSC remain poorly characterized, limiting the development of targeted therapeutic interventions. We systematically analyzed PCD patterns in HNSC using the GSE30784 dataset and identified BaP toxicity targets through comprehensive database mining. Machine learning algorithms, including RF and SVM, were employed to identify core toxic targets. Target validation was performed using the TCGA-HNSC cohort, followed by the construction of a prognostic nomogram. Mechanistic insights were obtained through spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), gene set enrichment analysis (GSEA), molecular docking, and molecular dynamics simulations to elucidate BaP-protein interactions. We identified ten distinct PCD modes significantly dysregulated in HNSC compared to normal tissues. Among 260 putative BaP targets, 24 demonstrated significant associations with PCD pathways in HNSC. Machine learning analysis revealed SERPINE1, TNFRSF10B, and STK3 as core mediators of BaP toxicity, with SERPINE1 emerging as the predominant driver of BaP-induced cellular dysfunction. The integrated nomogram achieved robust performance in cancer risk stratification. Spatial transcriptomic analysis demonstrated preferential enrichment of these targets in malignant epithelial cells, while scRNA-seq revealed cell type-specific expression patterns. GSEA identified enrichment in apoptotic signaling, TGF-β pathway activation, and DNA damage response mechanisms. Molecular docking studies revealed high-affinity binding interactions, with molecular dynamics simulations confirming stable BaP-protein complexes. This integrative multi-omics analysis elucidates the complex molecular architecture underlying BaP-induced toxicity in HNSC, establishing SERPINE1 and STK3 as promising prognostic biomarkers and potential therapeutic targets. Our findings provide mechanistic insights into environmental carcinogen-mediated HNSC pathogenesis and offer a rational framework for developing precision medicine approaches targeting BaP-associated malignancies.