What Drives Aggressiveness of Smoker Lung Adenocarcinoma? Potential Role of Nicotine-Responsive Neuropeptides Neurotensin and Calcitonin-Related Polypeptide Alpha.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of nonsmall cell lung cancer. Cigarette smoking, the primary etiological factor, introduces mutagenic and epigenetic changes that promote tumorigenesis, with nicotine acting as a key bioactive component modulating cellular signaling rather than directly causing mutations. In this study, differential transcriptomic profiling of smoker and nonsmoker LUAD samples from the PanCancer Atlas identified neurotensin () and calcitonin-related polypeptide alpha () as the most significantly upregulated genes in smokers. The analysis included 495 LUAD tumor samples with annotated smoking history, comprising 209 never smokers and 286 current smokers. A dataset from the NCBI Gene Expression Omnibus (GSE10072) was used to validate the results. Only samples from current smokers and never smokers were considered to unravel direct molecular impact of active smoking, and the analysis confirmed the observed differential expression patterns of key genes, including and , between smoker- and nonsmoker-derived LUAD samples. Pathway enrichment analysis revealed G protein-coupled receptor-mediated neuroendocrine signaling activation, suggesting a nicotine-driven reprogramming of tumor cells toward a secretory phenotype. Molecular docking simulations demonstrated stable interactions of (S)-nicotine with NTS and CALCA, suggesting these proteins as potential mediators of nicotine-induced oncogenic signaling. Kaplan-Meier analysis indicated that high expression of and was associated with poorer overall survival, warranting further investigation in independent cohorts. Collectively, this integrative bioinformatics and structural study informs the molecular consequences of smoking in LUAD, identifies nicotine-responsive neuropeptides as potential signatures of tumor aggressiveness, and can provide a foundation for drug repurposing strategies to mitigate smoking-associated malignancy.