Deciphering the molecular mechanisms of fluoxetine-induced sexual dysfunction: Evidence from pharmacovigilance,...

To evaluate the association between fluoxetine and sexual dysfunction using real-world pharmacovigilance data and to explore its potential molecular mechanisms through network toxicology and molecular docking.

Data from the FDA Adverse Event Reporting System (FAERS) from 2004 to 2025 were analyzed. Reports identifying fluoxetine as the primary suspected drug were included. Disproportionality analyses (ROR, PRR, MGPS, and BCPNN) and time-to-onset (TTO) analysis were performed. Potential drug and disease targets were identified from multiple databases, followed by GO and KEGG enrichment, protein-protein interaction analysis, and molecular docking.

A total of 997 fluoxetine-related adverse event reports were included. Significant disproportionality signals were observed between fluoxetine and multiple dimensions of sexual dysfunction, including decreased libido, erectile dysfunction, orgasmic disorders, and genital sensory abnormalities. Notably, orgasm-related and sensory-related adverse events demonstrated stronger signal intensities. TTO analysis revealed substantial temporal heterogeneity, with some events occurring early after drug initiation and others associated with long-term exposure. Network toxicology identified 56 overlapping targets, mainly enriched in neuroactive ligand-receptor interaction, dopaminergic synapse, serotonergic synapse, and inflammation-related pathways. PPI network analysis identified TP53 and IL10 as key hub genes. Molecular docking results demonstrated favorable binding affinities between fluoxetine and both IL10 and TP53, with stronger binding observed for IL10.

Fluoxetine-associated sexual dysfunction is multidimensional and may involve serotonergic overactivation, dopaminergic suppression, and neuroinflammatory and apoptosis-related mechanisms. IL10 and TP53 may serve as key targets, providing insights for safer clinical use and future mechanistic studies.