Plasma proteomic analysis identified potential therapeutic targets for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) remains a progressive disease with high mortality. By integrating the UK Biobank Pharma Proteomics Project (49,272 participants, 337 incident cases) with drug-target Mendelian randomization, we identified 398 plasma proteins associated with incident PAH and 19 with potential causal relevance, 15 of which are druggable. Then we prioritized 5 candidates for expression validation in the Sugen5416 and hypoxia rat model and confirmed significant upregulation of TNFRSF10A and downregulation of UMOD in lung tissue, consistent with human plasma proteomic trends. Subsequent in vitro functional assays demonstrated that UMOD treatment attenuates PAH-related cellular phenotypes, whereas TNFRSF10A knockdown exacerbates pro-pathogenic progression. These results suggest UMOD as a promising protective therapeutic candidate and indicate the inherent complexity of the TNFRSF10A signaling. This integrative study provides a robust framework for translational research, future studies are warranted to elucidate downstream molecular mechanisms and further evaluate the therapeutic efficacy of these candidates.