Multi-omics, molecular modeling and experimental analysis of carcinogen benzo(a)pyrene promoting the progression of laryngeal cancer.

Laryngeal cancer (LC) is one of the common malignant tumors in the upper respiratory tract. Polycyclic aromatic hydrocarbons (PAHs) are important pollutants widely present in the environment, among which benzo(a)pyrene (BaP) has been classified as a Class I carcinogen by the International Agency for Research on Cancer due to its strong carcinogenicity. However, how different PAHs recognize and act on key protein targets at the molecular level, as well as their potential common molecular interaction patterns, still lack systematic research. This study integrates chemical informatics, network toxicology, machine learning, and molecular simulation techniques to systematically analyze the mechanism of action of BaP and its structural analogues in laryngeal cancer, screening out 41 potential targets, which are enriched in the cell cycle and p53 signaling pathways. Through machine learning, CDK2, AURKA, PCYT1A, FADS1, and SLCO1A2 were identified as core targets, and it was found that these genes are significantly highly expressed in laryngeal cancer tissues and are closely related to tumor immune cell infiltration. Molecular docking and 200 ns molecular dynamics simulation showed that although the chemical structures of the three PAHs differ, they present highly consistent binding conformations and similar non-covalent interaction patterns, including hydrogen bonds, π–π stacking, and van der Waals forces. The conserved hydrophobic residues ILE10 and LEU134 form a stable hydrophobic interaction in the complex and contribute significantly to the binding free energy. Further kinetic simulation results indicated that the complex structure remained stable in the later stage and the overall binding mode had good kinetic stability. In summary, this study reveals from the chemical structure and molecular recognition perspective that PAHs regulate key protein functions through conserved binding sites and common interaction patterns, providing atomic-level evidence for the structure-effect relationship and molecular toxicological mechanism of environmental carcinogens.