Integrated bioinformatics and clinical validation reveals PRDX6 as a mitochondrial hub gene in systemic lupus erythematosus

Abstract Objectives Peroxiredoxin 6 (PRDX6), a potent antioxidant enzyme, has garnered considerable interest for its potential involvement in inflammatory diseases. However, the relationship between PRDX6 and SLE remains poorly understood. This study aims to elucidate the association between PRDX6 and SLE, providing insights into its potential role in disease mechanisms. Method Gene expression datasets (GSE50772, GSE61635) from the GEO database were merged and batch-corrected (sva, limma). DEGs were identified and SLE-associated gene modules were analyzed by weighted gene co-expression network analysis (WGCNA). Intersecting differentially expressed genes (DEGs), module genes, and MitoCarta3.0-defined mitochondria-associated DEGs, which were refined by LASSO, Random Forest, and SVM-RFE to select hub genes. The expression levels of PRDX6 in peripheral blood mononuclear cells (PBMCs) from SLE patients were measured by quantitative PCR and Western blot analysis. Results A total of 1581 DEGs (865 upregulated, 716 downregulated) were identified. WGCNA revealed a key module of 1615 genes; intersecting this module with DEGs and MitoCarta3.0 yielded 36 mitochondria-associated DEGs. Three machine learning methods narrowed these to 11 core genes, including PRDX6. The expression levels of PRDX6 were significantly lower in SLE PBMCs than in healthy controls, especially in active SLE. Patients with renal or joint involvement had lower PRDX6 levels. The mRNA levels of PRDX6 showed an inverse correlation with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Conclusions This study suggested that PRDX6 might be a potential biomarker and exert protective effects by reducing oxidative stress in SLE. Key Points • IFI27 and PRDX6 serve as potential mitochondrial-related biomarkers in SLE. • PRDX6 is significantly downregulated in SLE. • PRDX6 is associated with SLEDAI score.