Identification of key oxidative phosphorylation-related genes in systemic lupus erythematosus based on...

Oxidative phosphorylation (OXPHOS) dysfunction is increasingly recognized as a key factor in systemic lupus erythematosus (SLE) pathogenesis. This study aimed to identify OXPHOS-related core genes as potential SLE biomarkers and therapeutic targets.

mRNA sequencing and GSEA were performed on MRL/lpr mouse kidneys. Cross-species differentially expressed genes (DEGs) were identified by integrating mouse data with human SLE kidney datasets from the Gene Expression Omnibus (GEO). Overlapping DEGs with OXPHOS-related genes from GeneCards, a protein-protein interaction (PPI) network was constructed to screen core genes, followed by GO and KEGG enrichment analyses. Gene expression was validated in SLE whole blood, skin lesions, and immune cell subsets using independent GEO datasets. Diagnostic value was assessed by receiver operating characteristic (ROC) analysis; correlation with disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Drug-target interactions were analyzed via DrugBank and STRING. Key genes were validated by qPCR in MRL/lpr kidneys.

The OXPHOS pathway was significantly downregulated in MRL/lpr kidneys. Ten consistently upregulated core genes-CCNA2, KIF11, CDC20, TOP2A, TPX2, AURKB, DLGAP5, FOXM1, MKI67, and CEP55-were identified and enriched in cell cycle regulation and cellular senescence. All ten were upregulated in SLE blood; seven in skin lesions. They were broadly overexpressed in immune cells, especially plasmablasts and CD4⁺ T cells. CDC20, DLGAP5, and CEP55 showed high diagnostic accuracy (AUC >0.8). CCNA2 (r = 0.50) and CDC20 (r = 0.56) correlated significantly with SLEDAI. Six genes interacted with known SLE drug targets. Integrating expression and interaction profiles, CCNA2, AURKB, FOXM1, and MKI67 were prioritized as top therapeutic candidates. Quantitative real-time polymerase chain reaction (qPCR) confirmed CCNA2 and FOXM1 upregulation in MRL/lpr kidneys.

This study identifies a systemic OXPHOS-related gene signature in SLE, highlighting promising candidates for diagnosis and targeted therapy.