Abstract
Background: Systemic lupus erythematosus (SLE) is characterized by aberrant immune activation and disrupted iron metabolism, yet the molecular mediators that govern both processes remain unclear. This study aims to identify pivotal genes that modulate immune responses and iron metabolism, and to delineate their contributions to SLE pathogenesis. Methods: Differentially expressed genes related to iron metabolism (IM-DEGs) were identified using datasets (GSE72326, GSE110169, GSE126307, and GSE50772) from the GEO database and the MSigDB. Functional enrichment analyses were performed on the iron metabolism related genes (IM-Genes). A weighted gene co-expression network analysis was constructed to identify hub genes, which were further refined as potential biomarkers using the least absolute shrinkage and selection operator method. The predictive value of these biomarkers was validated using receiver operating characteristic (ROC) curves and the nomogram. CIBERSORT was employed to evaluate immune cell infiltration in SLE. Additionally, the expression and function of RSAD2 were confirmed using RNA interference, quantitative real-time PCR, and Western blotting techniques. Results: Bioinformatics analyses identified 4 potential biomarkers: RSAD2, MT2A, LCN2, and LTF. RSAD2 exhibited the highest clinical validity (AUC = 0.927) and was closely associated with classic diagnostic indicators. Its diagnostic potential was confirmed through ROC curve and nomogram, highlighting its role in SLE pathogenesis. Elevated RSAD2 expression was observed in peripheral blood mononuclear cells of SLE patients, positively correlating with activated dendritic cells (DCs). Notably, Rsad2 knockdown markedly impaired the function of activated DCs, as evidenced by suppressed expression of inflammatory mediators and iron metabolism-related genes. Conclusion: Our findings suggest that RSAD2 is a potential diagnostic biomarker and therapeutic target for SLE, elucidating the intricate relationship between immune dysregulation and aberrant iron metabolism in activated DCs, which exacerbates SLE.