Deciphering Nicotine-Driven Oncogenesis in Head and Neck Cancer: Integrative Transcriptomics and Drug Repurposing Insights

<b>Background</b>: Chronic nicotine exposure drives head and neck cancer (HNC) progression, yet its molecular mechanisms remain underexplored. This study examines nicotine-induced transcriptomic changes and potential therapies via drug repurposing. <b>Methods</b>: HNC cell lines (OECM1, SAS, and CGHNC9) were exposed to an IC30 nicotine dose for three months to model chronic exposure in habitual smokers. Transcriptomic profiling of these sublines was integrated with TCGA-HNSC patient data. Differentially expressed genes (DEGs) underwent functional pathway enrichment analysis. Drug repurposing was conducted using gene-drug correlation analysis across GDSC, CTRP, and PRISM databases. <b>Results</b>: Transcriptomic analysis identified 1223 DEGs in nicotine-exposed HNC cells, and integration with TCGA-HNSC data defined a Nic-HNC gene set of 168 genes: 149 oncogenes and 19 tumor suppressors, with 36 oncogenes overexpressed in heavy smokers. Pathway analysis revealed the upregulation of oncogenic signaling, such as PI3K-AKT, alongside the suppression of immune regulation and metabolic reprogramming. Drug repurposing identified five compounds-AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide-with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC. <b>Conclusions</b>: This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine's oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC.