A proteogenomic atlas of idiopathic pulmonary arterial hypertension reveals sex-dimorphic mechanisms and potential novel therapeutic targets

Current circulating biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack specificity for preclinical detection and fail to capture the biological heterogeneity driving disease progression. Furthermore, molecular mechanisms underlying the “sex paradox” of IPAH, where females exhibit higher susceptibility but lower mortality, remain poorly understood, hindering the development of precision therapeutics. We performed an integrated proteogenomic analysis characterizing 2,920 plasma proteins from 45,811 participants in the UK Biobank. We integrated discovery-driven Cox regression with case-control verification, followed by cis-Mendelian randomization and colocalization to distinguish causal mediators from bystanders. We utilized unsupervised clustering for biological risk stratification and machine learning to deconvolute sex-dimorphic proteomic signatures, finally applying systemic drug reproposing to prioritize therapeutic candidates. We identified 92 causal proteins driving IPAH incidence (e.g., NOTCH3, FLT3IG) and 15 driving mortality (e.g., REG4, CA6), with 9 proteins (e.g., EDN1, LRRN1) serving as dual determinants. Unsupervised clustering identified a high mortality-risk phenotype characterized by upregulated proteins associated with extracellular matrix-receptor interaction, transforming growth factor-β signaling, cardiac hypertrophy, and elastic fibre formation, together with reduced plasma levels of APOL1. Notably, sex-stratified analysis revealed divergent pathogenic architectures that progression of IPAH in males was predominantly linked to right ventricular dysfunction mediators (e.g., NT-proBNP, GDF15), whereas in females, it was more strongly driven by vascular dysfunction mediators (e.g., EDN1, BCL2L15). Finally, we prioritized 27 druggable targets, with genetic evidence highlighting AGRN, CLU, and DDR1 as high-confidence candidates for therapeutic intervention. This study delineates causal proteomic landscape of IPAH, bridging epidemiological associations with genetically supported targets. By uncovering the molecular basis of sex-dependent outcomes and prioritizing novel druggable proteins, our findings provide a robust framework for preclinical detection, innovative risk stratification, and the development of precision therapeutics.