Machine learning and multi-dimensional transcriptomics reveal the key molecular network of benzo(a)pyrene/NNK in...

Benzo(a)pyrene (BaP) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as typical environmental carcinogens, are widely present in tobacco smoke and air pollution. Their combined exposure is an important cause of high incidence of laryngeal cancer. However, the molecular mechanism of their synergistic carcinogenesis remains unclear. To fill this gap, this study employed an integrated strategy combining network toxicology, multi-dimensional transcriptomics (bulk and single-cell), machine learning, molecular simulation, and cell function verification to systematically explore the mechanism by which BaP and NNK combined exposure induce laryngeal cancer. Through multi-dimensional data mining and machine learning algorithms, the core molecule FADS1 was identified. Functional enrichment analysis revealed that FADS1-related genes mainly participate in lipid metabolism reprogramming and tumor malignant phenotype regulation pathways. Molecular docking and 100 ns kinetic simulation confirmed that both BaP and NNK can stably bind to FADS1, with a stronger binding affinity for BaP (ΔG = -9.0 kilocalories/mole), and the binding mode is mainly based on van der Waals forces and hydrophobic interactions. Cell experiments demonstrated that combined exposure of BaP and NNK can significantly upregulate the expression of FADS1 in laryngeal cancer cells, enhance cell proliferation, migration, and invasion abilities, while silencing FADS1 can effectively reverse these malignant phenotypes. In summary, this study clarified the key role of FADS1 in mediating the synergistic promotion of laryngeal cancer by BaP/NNK, providing experimental support for understanding the carcinogenic mechanism of environmental compound pollutants, and also offering potential targets for risk assessment, early diagnosis, and precise prevention and control of air pollution and tobacco exposure-related laryngeal cancer.