Dysregulated fibroblast-immune crosstalk drives statin-associated erectile dysfunction: integrative evidence from...

Mounting evidence points to a potential link between statin therapy and erectile dysfunction (ED). However, the underlying mechanisms remain elusive, particularly concerning potential statin disruption of the inflammatory and immunofibrotic microenvironment within erectile tissue. This study sought to elucidate statin-associated ED and identify key molecular and cellular mediators driving this process.

An integrative strategy merging real-world pharmacovigilance, network pharmacology, and toxicological analyses was deployed to explore drug-associated ED. Drug-related and disease-associated targets were intersected and scrutinized using protein-protein interaction (PPI) networks to pinpoint key regulatory genes. Gene expression patterns were evaluated through bioinformatics analyses and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Molecular docking and molecular dynamics (MD) simulations assessed drug-target interaction stability. Furthermore, single-cell RNA sequencing (scRNA-seq) analysis characterized cell-type-specific alterations and intercellular communication dynamics within erectile tissue.

Disproportionality analysis identified atorvastatin (ROR = 3.36, 95% CI = 3.04-3.70) and rosuvastatin (ROR = 3.22, 95% CI = 2.81-3.69) as statins significantly linked to ED, exhibiting moderate predicted toxicity. Four key genes-FGFR1, SERPINE1, TGFB2, and TGFBR2-emerged as potential mediators connecting statin exposure to ED. FGFR1 expression plunged significantly, while SERPINE1 expression surged markedly in ED samples, findings consistently observed in both transcriptomic analyses and RT-qPCR validation. Molecular docking and MD simulations demonstrated stable binding between atorvastatin and FGFR1. Notably, scRNA-seq analysis revealed fibroblasts as central immunomodulatory cells in ED, with their intercellular communication dysregulation closely related to the abnormal activation of the FGFR1 axis, which further mediates the local immunofibrotic disorder of the corpus cavernosum.

This study delivers convergent evidence that atorvastatin and rosuvastatin associate with ED and implicates dysregulated inflammatory and immunofibrotic remodeling of erectile tissue as a potential underlying mechanism. The identified key genes and fibroblast-centered cellular interactions yield fresh insights into statin-associated ED and highlight promising molecular targets for future translational and immunomodulatory therapeutic strategies.