Objective To evaluate the association between paroxetine exposure and breast cancer risk by using a multi-omics approach and to elucidate the underlying molecular mechanisms.

Methods A cross-sectional analysis was conducted using NHANES data from 2005 to 2016 to assess paroxetine exposure and breast cancer prevalence. Network pharmacology was employed to identify common targets and pathways, followed by Mendelian randomization analysis to validate causal relationships and molecular docking to further verify key interactions.

Results Among 5520 participants, paroxetine users showed a 270% increased risk of breast cancer after multivariate adjustment (adjusted OR=3.70, 95%CI: 1.15-11.99, P=0.032). Network pharmacology identified 92 overlapping targets, with mTOR emerging as a central hub (IVW OR=1.09, 95%CI: 1.06-1.13, P=6.67×10⁻⁷). Molecular docking confirmed a high-affinity binding between paroxetine and mTOR (binding energy: −8.3 kcal/mol). Pathway enrichment analysis indicated that the PI3K-Akt signaling pathway, endocrine resistance, and chemical carcinogenesis were key mechanisms.

Conclusion Paroxetine use may be linked to an increased risk of breast cancer, possibly mediated through the mTOR pathway.