Transcriptomic profiling reveals immune pathway dysregulation and key interferon-responsive genes in Systemic Lupus...

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder characterized by chronic inflammation, multi-organ involvement, and a strong type I interferon (IFN) signature. To elucidate immune-specific molecular drivers of SLE, we performed transcriptomic profiling using RNA sequencing (RNA-seq) data from 117 samples (99 SLE patients, 18 healthy controls) obtained from the European Nucleotide Archive (PRJNA294187). Following quality control, alignment to GRCh38, and read quantification, differential expression analysis with DESeq2 identified 2150 differentially expressed genes (DEGs), including 1361 upregulated and 789 downregulated genes (FDR<0.01, |log₂FC=>1). Reactome pathway enrichment isolated 41 immune-related DEGs enriched in cytokine signaling, interferon response, antigen processing, and innate immune activation. Notably, interferon-stimulated genes (ISGs) such as EIF2AK2, ISG15, CXCL10, CXCL11, IFI44L, RSAD2, and HERC5 emerged as central nodes in immune regulatory networks. Gene Ontology analysis highlighted overactivation of defense response, chemokine-mediated cell trafficking, and Jak-STAT signaling pathways typically induced by viral infection but aberrantly sustained in SLE, driving chronic inflammation and autoimmunity. Several genes, including HERC5, HERC6, and IL5RA, exhibited regulatory roles in ubiquitination and cytokine receptor signaling, suggesting potential as biomarkers for disease activity. These findings support targeting type I IFN signaling and related immune circuits as therapeutic strategies, aligning with emerging clinical success of IFN-blockade in SLE. By prioritizing immune-focused DEGs and integrating pathway-level interpretation, our study refines the transcriptomic landscape of SLE and provides actionable molecular insights for precision medicine approaches aimed at disease modulation and patient stratification.