Mechanisms in the transition from systemic lupus erythematosus to lupus nephritis: A bioinformatics and functional analysis approach

Lupus nephritis (LN), a severe renal complication of systemic lupus erythematosus (SLE), represents the primary driver of end-stage renal disease and mortality in SLE populations. Current immunosuppressive therapies carry significant comorbidity risks, underscoring the urgent need for non-invasive biomarkers enabling early LN detection. This study employed integrated bioinformatics approaches to identify circulating biomarkers predictive of SLE-to-LN transition. Analysis of the GSE99967 dataset revealed peripheral blood-derived differentially expressed genes (DEGs) between LN patients and SLE controls. Through weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network construction, we identified hub genes subsequently refined via three machine learning algorithms: LASSO regression, random forest, and SVM-RFE. Functional enrichment analyses using DAVID, GO, and KEGG pathways elucidated immune-related biological processes. The diagnostic performance of candidate biomarkers was rigorously validated through ROC curve evaluation across both training (GSE99967) and independent validation (GSE82221) cohorts, complemented by immune infiltration profiling to delineate cellular correlations. Our multi-modal approach consistently identified inducible T-cell costimulator (ICOS) as a pivotal biomarker, demonstrating superior diagnostic accuracy (AUC [specify value] in training, [value] in validation sets) for LN progression prediction. Mechanistically, ICOS expression patterns showed significant associations with Th cell subset infiltration, suggesting its dual role as both diagnostic indicator and immunopathogenic mediator. These findings position ICOS as a promising non-invasive biomarker capable of guiding early therapeutic intervention and personalized management of SLE patients at risk for nephritis progression, potentially circumventing the need for invasive renal biopsies while addressing critical unmet needs in lupus nephropathy surveillance.