Pulmonary arterial hypertension (PAH) is a rare but severe complication of systemic lupus erythematosus (SLE). Patients with SLE-associated PAH exhibit significantly reduced long-term survival compared to those without PAH. Currently, the molecular indicators used in clinical practice to evaluate SLE-associated PAH are nonspecific under the premise of SLE as the underlying disease. A more comprehensive understanding of the biomarkers for SLE-associated PAH is crucial for the potential early diagnosis and new therapeutic targets.

Patients diagnosed with SLE-associated PAH (SLE-PAH) and SLE without PAH (SLE-nPAH) and healthy controls (HC) were respectively recruited from the Chinese SLE Treatment and Research Registry (CSTAR) as discovery cohort, repeated cohort and validation cohort. Clinical data, laboratory testing and plasma sample were collected. We employed the data-independent acquisition (DIA) technique for quantitative proteomics, and hierarchical clustering and pathway enrichment analysis to systematically characterize shared and specific molecular features across different groups. Proteins with an FDR-adjusted p value below 0.05 and a fold change (FC) >2 or <0.5 were considered as differentially expressed proteins (DEPs). Significant DEPs were validated by enzyme-linked immunosorbent assay (ELISA) and clinical correaltion analysis.

In the discovery cohort (SLE-nPAH = 35, SLE-PAH = 49, HC = 50) and repeated cohort (SLE-nPAH = 45, SLE-PAH = 42, HC = 50) , 12 proteins were detected to have specific upregulation or downregulation in SLE-PAH, comparing with SLE-nPAH and HCs. KEGG pathway analysis revealed common dysregulation in some pathways, like adherens junction and cell adhesion molecules. In the validation cohort (SLE-nPAH = 52, SLE-PAH = 59) , patients with SLE-PAH had had significantly higher HLA-C (p=0.0425), ITGA2 (p=0.0011), ACP5 (p=0.0044), PPIC (p<0.0001), TWSG1 (p=0.0014), PGA3 (p=0.0112), PPP1CA (p=0.0255)  expression than SLE-nPAH. These DEPs had positive correlation with BNP, NT-proBNP or pulmonary vascular resistance (PVR) level of SLE-PAH patients. Among them, ITGA2 is related to endothelial cell proliferation, while TWSG1 is related to the balance of TGF-β/BMP pathway, which deserves further verification.

Our work identified specific proteins associated with SLE-PAH patients. Additional efforts are necessary to validate these proteins as clinically useful biomarkers and the underlying mechanisms.