Dysregulated fibroblast-immune crosstalk drives statin-associated erectile dysfunction: integrative evidence from pharmacovigilance and single-cell transcriptomics
Abstract
Background: 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.
Methods: 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.
Results: 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…
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