Pulmonary arterial hypertension (PAH) is a life-threatening vascular complication of systemic lupus erythematosus (SLE). In Asian populations, particularly in China, SLE is the most prevalent connective tissue disease underlying PAH. Despite its high morbidity, the shared immune mechanisms and molecular cross-talk between SLE and PAH remain incompletely elucidated. Prevailing evidence suggests that dysregulated immune responses and chronic inflammation may critically drive the pulmonary vascular remodeling characteristic of PAH. This study aimed to identify shared gene expression signatures and immune pathways mediating SLE-associated PAH using integrative bioinformatics analysis of public transcriptomic datasets. 

We conducted an integrative bioinformatics analysis using publicly available transcriptomic datasets from the GEO database. Differentially expressed genes (DEGs) were identified for both diseases, and weighted gene co-expression network analysis (WGCNA) was performed to isolate significant gene modules. We integrated these findings to construct protein-protein interaction (PPI) networks and identify core hub genes via the MCODE plugin. Furthermore, immune cell infiltration was evaluated using CIBERSORTx, and regulatory networks involving transcription factors (TFs) and microRNAs were analyzed to understand upstream control.

We identified six hub genes (STAT1, SERPING1, IFI27, IFI44L, IFIT1, and IFIT3), most of which are interferon-stimulated genes (ISGs). Functional enrichment analysis highlighted the central roles of type I interferon (IFN-I) signaling, antiviral responses, and cytokine-mediated pathways. Immune infiltration profiling revealed a significant increase in monocytes and macrophages in both diseases, which positively correlated with hub gene expression. We observed that IFN signaling potentially triggers complement activation and monocyte recruitment, leading to endothelial injury and smooth muscle cell proliferation. This interplay creates a vicious inflammatory cycle, culminating in a defined IFN-monocyte-complement pathogenic axis. Diagnostic evaluation via ROC curves confirmed the high sensitivity and specificity of these hub genes as potential biomarkers.

This study establishes the IFN-monocyte-complement axis as a core driver of SLE-associated PAH. The identified hub genes provide novel insights into the disease pathogenesis and represent promising diagnostic biomarkers and therapeutic targets.