Integrated network toxicology and immune profiling identify ESR1 as a potential hub linking Benzo[a]pyrene exposure to gastric cancer risk

OBJECTIVE: To elucidate the molecular mechanisms of Benzo[a]pyrene (BaP)-induced gastric cancer (GC) and identify core regulatory targets as potential biomarkers for GC. METHODS: The chemical structure and physicochemical properties of BaP were obtained from PubChem, ProTox, and ChEMBL databases, along with its active targets. GC-related pathogenic targets were retrieved from GeneCards, OMIM, and TTD. Intersecting targets between BaP and GC were identified, and a "BaP-intersecting targets-GC" ternary regulatory network was constructed. Functional enrichment analysis was performed on the intersecting targets, and a protein-protein interaction (PPI) network was built. Core targets were screened using the Degree algorithm, and their expression differences in GC were validated. The prognostic value of these targets was assessed using Kaplan-Meier survival curves. Immunofluorescence was used to determine the subcellular localization of core targets, and their roles in immune infiltration and genetic mutations were preliminarily explored. Finally, molecular docking was employed to reveal the potential interaction between BaP and core targets at the molecular structural level. RESULTS: ), acting as a potential protective factor (HR = 0.81, 95% CI: 0.66-0.99). Immune infiltration results indicated that ESR1 was closely related to immune cells such as T cells (R = 0.583), B cells, DC, and Tcm (all P < 0.001). Genetic mutation landscape analysis revealed that mutations in genes like TTN (highest mutation rate), TP53, and LRP1B were associated with ESR1 expression status in GC. Molecular docking demonstrated strong binding activity between BaP and ESR1, with a high-affinity conformation (Vina score=-11.2 kcal/mol). CONCLUSION: In conclusion, our integrated computational study provides preliminary evidence suggesting ESR1 as a potential hub linking BaP exposure to gastric cancer risk, possibly via influencing immune features. This identifies ESR1 as a candidate biomarker and reveals a testable hypothesis for future mechanistic investigation.