Uncovering the molecular network of nicotine induced erectile dysfunction through network toxicology and mendelian randomization.

BACKGROUND

In recent years, smoking has been recognized as a major risk factor for erectile dysfunction (ED). However, the specific harmful constituents of tobacco and their underlying molecular mechanisms remain poorly understood. This study aimed to systematically elucidate the potential targets and pathways of nicotine, the principal addictive component of cigarettes, in the development of ED using an integrative multi omics approach.

METHODS

Potential nicotine and ED related targets were identified via SEA, TargetNet, and SwissTargetPrediction databases, followed by intersection and enrichment analyses. PPI networks, GO, and KEGG analyses were used to identify key biological pathways. Transcriptomic datasets from rat ED models were integrated for differential expression and receiver operating characteristic (ROC) curve analyses. Mendelian randomization (MR) assessed causal relationships between gene expression and ED risk, while molecular docking validated ligand-receptor binding.

RESULTS

Thirty-four overlapping nicotine-ED related genes were identified, mainly enriched in dopaminergic and serotonergic signaling pathways. Four hub genes CNR1, HTR2A, HTR3A, and SLC6A4 were screened, with HTR3A showing the strongest association with ED. MR analysis revealed that higher HTR3A expression was significantly associated with reduced ED risk (OR = 0.607, 95 % CI: 0.454-0.811, p = 0.001). Molecular docking confirmed stable binding between nicotine and the HTR3A orthosteric pocket (binding energy = -6.8 kcal/mol).

CONCLUSIONS

HTR3A acts as a potential protective target in nicotine-induced ED. The proposed nicotine-HTR3A-serotonin signaling axis provides new mechanistic insights into smoking-related ED and suggests novel directions for precision prevention and therapeutic intervention.