Protein biomarkers in pulmonary arterial hypertension: advances, clinical relevance, and translational challenges

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pulmonary vasoconstriction and right ventricular dysfunction. Although classical circulating biomarkers such as brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are widely used in clinical settings, their low specificity and substantial variability limit their diagnostic and prognostic accuracy. In recent years, emerging protein biomarkers, such as Apelin, Osteopontin, and Endostatin, have provided deeper insight into disease mechanisms but require further validation. The advent of high-throughput proteomic platforms, including SOMAscan, Olink, and mass spectrometry-based assays, has revolutionized biomarker discovery by enabling the identification of novel candidates with greater sensitivity and specificity. Several proteomics-discovered biomarkers, including LTBP-2, IGFBP family members, NET4, TSP2, and FGF-23, have demonstrated superior prognostic value and may complement or surpass current standards in risk stratification. In this review, we comprehensively examine the landscape of circulating protein biomarkers in PAH, compare key proteomic technologies, and highlight translational challenges such as assay standardization and cohort heterogeneity. We propose an integrative approach combining proteomic, imaging, and genomic data to enhance precision diagnostics and personalized treatment strategies for patients with PAH.