Elucidating targets and mechanisms of dietary mycotoxin carcinogenesis via network toxicology, pan-cancer analysis, and molecular simulation.

Aflatoxins are widespread dietary contaminants with potent carcinogenicity, yet the molecular mechanisms of most congeners beyond AFB1 remain poorly characterized. To systematically elucidate the carcinogenic targets and mechanisms of five dietary aflatoxins-AFB1, AFB2, AFG1, AFG2, and AFM1-through network toxicology, pan-cancer analysis, and molecular docking. Toxicity was predicted using ProTox-3.0. Potential targets were identified from multiple databases, followed by GO and KEGG enrichment analyses. PPI networks were constructed, and core genes were identified using six topological algorithms. Pan-cancer expression, mutation, and survival were analyzed using TCGA and GTEx data. Immune infiltration, single-cell functional analyses, and molecular simulation were performed. All five aflatoxins were active carcinogens (0.59-0.68). Fifty-one common targets were identified, enriched in GPCR signaling and neurotransmitter pathways. Cross-analysis with cancer genes yielded 23 overlapping genes, with PTGS2, PIK3CA, and HSP90AA1 as core targets. These genes were differentially expressed across multiple cancers and associated with survival. PIK3CA showed the highest mutation frequency (89%). Immune infiltration revealed negative correlations with CD8 + T cells and positive with Tregs. Molecular simulation confirmed effective potential binding. PTGS2, PIK3CA, and HSP90AA1 are core carcinogenic targets of dietary aflatoxins, demonstrating that multiple congeners share common carcinogenic pathways with implications for food safety risk assessment.