Advancing PCOS drug development: multi-omics discovery of key targets and repurposable compounds.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in reproductive-age women, characterized by limited therapeutic options that address its underlying mechanisms. This study aimed to identify novel druggable protein targets for PCOS using a multi-omics integrative approach. Proteome-wide association studies (PWAS)-Mendelian randomization (MR) and summary-based MR (SMR) analyses were performed on large-scale plasma proteomics data from deCODE and UK Biobank cohorts, integrated with PCOS genome-wide association study (GWAS) summary statistics to screen for causal associations. Validation and prioritization involved Bayesian colocalization, transcriptome-wide association studies (TWAS), methylome-wide association studies (MWAS), and Gene Expression Omnibus (GEO) differential expression analysis. Biological mechanisms, druggability, and potential side effects were evaluated through protein-protein interaction networks, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment, single-cell expression profiling, drug prediction via DSigDB, molecular docking, and MR-phenome-wide association studies (PheWAS). Fifty-seven candidate proteins were nominally associated with PCOS risk. FSHB met the stringent high-colocalization criterion (PPH4 > 0.8), whereas THOP1, CAMKK1, PDLIM4, and ERBB4 met the broader colocalization criterion (PPH3 + PPH4 > 0.8). After robustness filtering, ERBB4 was retained as a secondary candidate, and THOP1, FSHB, CAMKK1, and PDLIM4 were prioritized as tier 1 targets, with pathway analyses implicating lysosomal and MAPK-related processes. Drug predictions identified compounds such as Triciribine and 1,3,5(10)-Estratriene-2,3-diol-17-one, demonstrating favorable docking affinities (e.g., - 9.7 kcal/mol for FSHB). MR-PheWAS indicated limited side effects for most targets, except for FSHB-associated reproductive risks. These findings offer robust evidence for prioritized therapeutic targets, facilitating advancements in precision medicine and drug development for PCOS.