The effects of nicotine exposure on depression: An integrative analysis combining network toxicology, molecular docking, and Mendelian randomization

INTRODUCTION: Depression is a globally prevalent affective disorder closely associated with environmental factors and neurological dysfunction, affecting over 300 million people worldwide and imposing a heavy burden on families and healthcare systems. As the core addictive bioactive component in tobacco, nicotine is intimately linked to an increased risk of depression, but its underlying molecular mechanisms remain unclear. This study aimed to explore the molecular mechanisms of nicotine-induced depression and identify the core molecular targets and pathways involved. METHODS: This study integrated network toxicology, molecular docking, and Mendelian randomization (MR). Nicotine's structure and SMILES were retrieved from PubChem for toxicity analysis via ADMETlab 3.0 and Protox3.0. Potential targets of nicotine and depression-related genes were screened from databases including GeneCards, OMIM, and ChEMBL. Common targets were obtained via Venny for PPI network construction, core target screening, GO/KEGG enrichment analysis, and molecular docking of the top 5 targets. MR verified causal associations with depression. RESULTS: Nicotine exhibited significant neurotoxicity (probability=0.951), respiratory, hepatotoxic, and nephrotoxic effects. A total of 69 common targets were identified, including DRD2, CHRNA4, and STAT3. GO enrichment involved biological processes like excitatory postsynaptic potential and KEGG pathways such as cAMP signaling. Molecular docking showed favorable binding affinity (binding energies < -5.0 kcal/mol). MR confirmed that higher CHRNA4 expression in the Nucleus Accumbens increased depression risk (IVW, OR=1.02; 95% CI: 1.01-1.04, p=0.003). CONCLUSIONS: This study demonstrated that nicotine exacerbates depressive-like behaviors by binding to core targets, including DRD2 and CHRNA4, and regulating dopaminergic and cholinergic pathways. These findings provide mechanistic insights for elucidating the underlying molecular mechanisms of nicotine-induced depression, while the identified targets and pathways offer potential directions for subsequent mechanistic validation and targeted studies of depression associated with nicotine exposure.