Repurposing piroxicam as an SLC7A5 antagonist to ameliorate prothrombotic state in Diane-35-treated polycystic ovary syndrome patients.

This multidisciplinary investigation employed an integrated clinical-translational framework to comprehensively evaluate the efficacy and treatment-emergent thrombotic risk of Diane-35 in polycystic ovary syndrome (PCOS). In a prospective self-controlled cohort of 103 patients, Diane-35 therapy led to significant endocrine improvements-including marked reductions in free androgen index (FAI) and luteinizing hormone-to-follicle-stimulating hormone ratio-but also induced a prothrombotic phenotype characterized by elevated D-dimer (DD) levels. To decipher the genetic basis of thrombosis, we applied multivariable Mendelian randomization (MVMR) across distinct arterial embolism and thrombosis endophenotypes, identifying the solute carrier family 7 member 5 (SLC7A5) as a novel and robust genetic determinant. Causal inference was rigorously validated via summary-based MR (SMR), Bayesian colocalization (PPH4 = 0.91), and cis-protein quantitative trait loci mapping, confirming its central role in the pathogenesis of vascular complications. Using the coarse-grained molecular dynamics simulations via the CABS-flex 2.0 platform, we characterized residue-level flexibility and identified conformationally responsive binding pockets within SLC7A5. Structure-based virtual screening integrated with comprehensive ADME-toxicity profiling identified piroxicam as a high-affinity, selective SLC7A5 inhibitor (Vina score = -9.3 kcal/mol) with favorable pharmacokinetics and minimal pleiotropy risk, which further supported by the phenome-wide association scanning. This study elucidate a novel genetically informed mechanism for Diane-35-associated thrombosis and propose targeted SLC7A5 inhibition as a promising therapeutic strategy. Piroxicam emerges as a mechanistically grounded repurposing candidate for mitigating thrombotic risk in PCOS, effectively bridging genomic discovery with clinical intervention.