Proteogenomic Profiling of Idiopathic Pulmonary Arterial Hypertension Identifies Sex-Differential Proteins and Candidate Therapeutic Targets.

Authors

Xinjie Lin, Yangchang Zhang, Yang Pu, Duanke Liu, Tao Lei, Kai Ma, Qiyu He, Zheng Dou, Yuze Liu, Dengyuan Liu, Yinge He, Yanshang Wang, Xiaojiao Zheng, Yanbing Ma, Jianrong Zhou, Weiding Zhai, Binbin Su, Li Chen, Shoujun Li

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77687. Sep 16, 2026. Epub Sep 16, 2026.

Abstract

Current biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack disease specificity and provide limited biological insight. We hypothesized that integrating population-based proteomics with genetic evidence would identify robust IPAH-associated proteins relevant to risk stratification, early detection, prognosis, sex differences, and candidate drug-repurposing opportunities.
We analyzed 2,918 plasma proteins in 44,137 predominantly European-ancestry UK Biobank participants aged 40-69 years, including 252 incident and 141 prevalent IPAH cases. Proteins associated with IPAH were identified using Cox and logistic regression analyses, prioritized by cis-Mendelian randomization, and assessed through cross-ancestry effect-direction concordance and sensitivity analyses. Unsupervised clustering, nested cross-validated prediction models, and target-drug annotation were used for downstream evaluation.
Eighteen proteins showed convergent epidemiological and genetic evidence, and 12 remained supported in cross-ancestry and sensitivity analyses. These proteins defined a high-mortality endotype characterized by vascular and ventricular remodeling. Combined clinical and proteomic models achieved AUCs of 0.779 for incident IPAH and 0.768 for mortality. Proteomic contributions differed by sex, and target-drug annotation identified six drug-linked proteins, highlighting ANXA2-linked Artenimol as a repurposing candidate.
Twelve biologically plausible IPAH-associated proteins inform risk stratification, prediction, sex-related characterization, and therapeutic prioritization. Independent multi-ancestry validation and mechanistic studies are warranted.

PMID:
42750184
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.

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