Deciphering benzo[a]pyrene-induced lung adenocarcinoma mechanisms via bioinformatics analysis

Benzo[a]pyrene (BaP), a widespread environmental carcinogen derived from sources such as cigarette smoke, fossil fuel combustion, and high-temperature cooking, primarily enters the human body through inhalation, dermal contact, and dietary intake. Strong evidence implicates BaP as a pivotal risk factor in the initiation of lung adenocarcinoma (LUAD), a major subtype of lung cancer and the leading cause of global cancer-related mortality. However, the systemic molecular mechanisms underlying BaP-induced LUAD remain incompletely understood. This study employed an integrated approach combining bioinformatics analysis with molecular docking to elucidate the pathogenic role of BaP in LUAD. We identified 78 potential targets, among which eight core targets (CYP3A4, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, ESR1, and PTGS2), were functionally enriched in processes related to cell proliferation/migration, transcription factor binding, and immunomodulation. Molecular docking demonstrated spontaneous binding of BaP to all core targets via π-π stacking and cation-π interactions. Experimentally, BaP exposure elevated intracellular ROS levels in A549 cells in a concentration-dependent manner, and fluorescence quenching assays confirmed direct interactions of BaP and core targets. Mechanistically, BaP promotes LUAD through a coordinated multi-network model involving metabolic activation (via CYP450 enzymes), DNA damage, inflammatory signaling (centered on PTGS2), and hormone-mediated pathways (via ESR1). These findings provide a systemic, multi-target perspective on BaP-induced LUAD pathogenesis and offer a theoretical foundation for developing targeted prevention and therapeutic strategies. • The mechanism of BaP-induced LUAD was revealed via network toxicology • Protein targets of BaP toward LUAD were identified. • CYP450s, PTGS2, and ESR1 work together to induce LUAD. • Determination of the molecular binding of BAP to core targets.