An integrated network toxicology and multi-omics framework prioritizes BRCA1 as a testable candidate in benzo[a]pyrene-associated oral cancer

Abstract

Environmental exposure to benzo[a]pyrene (BaP) is a recognized risk factor for oral cancer, but systematic strategies for prioritizing candidate molecular nodes and generating experimentally testable hypotheses remain limited. Here, we conducted a hypothesis-generating, methodologically oriented exploratory study using an integrated three-tier framework comprising computational target prioritization, multi-omics contextualization, and preliminary phenotypic assessment. Network toxicology identified four genes shared between the predefined BaP-associated and oral cancer-related gene sets: EGFR, HRAS, TP53, and BRCA1. These genes constituted the complete intersection and were not ordered by a composite score. BRCA1 was selected as a study-specific, testable candidate for focused follow-up based on convergent expression, protein-context, and DNA-damage-response evidence. Exploratory docking and molecular dynamics analyses characterized a predicted BaP–BRCA1 structural model but did not establish direct biochemical binding. Single-cell and spatial transcriptomic analyses described the baseline distribution of BRCA1 across tumor, immune, and stromal compartments but lacked BaP exposure annotations. Separately, BaP treatment was accompanied by increased proliferation and BRCA1 mRNA expression in CAL27 and SCC9 cells, whereas BRCA1 knockdown attenuated BaP-associated proliferation and was accompanied by changes in p53-axis transcript and protein readouts. This exploratory study prioritizes BRCA1 as a testable candidate and illustrates the utility of integrating network toxicology with multi-omics contextualization. The current findings do not establish direct BaP–BRCA1 binding, direct regulation of BRCA1 by BaP, a definitive in vivo mechanism, or clinical causality. All mechanistic and clinical interpretations require further validation through direct biochemical assays, additional experimental models, and exposure-annotated human cohorts.