Identifying Crucial Genes Associated with Pyroptosis in Lupus Nephritis

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, involves immune complex deposition, inflammation, and kidney damage. Recent studies indicate that pyroptosis, a pro-inflammatory cell death process, drives renal injury in LN. This study intended to identify key pyroptosis-related genes in LN using datasets from the GEO database, encompassing glomerular, tubulointerstitial, and whole kidney tissues from LN patients. Identified differentially expressed genes related to pyroptosis and created a predictive model using univariate and LASSO regression analysis. LN patients were classified into subtypes through consensus clustering. Immune microenvironment characteristics and hallmark pathways were further analyzed. Using the WGCNA, key gene modules and hub genes were recognized, followed by an analysis of their clinical relevance and distribution patterns using the Nephroseq database and scRNA-seq data. Cellular experiments were conducted to validate the findings. We identified 26 differentially expressed pyroptosis-related genes in LN glomeruli and created a 10-gene model with high diagnostic accuracy (AUC: 0.968 for tubulointerstitium, 0.990 for whole kidney). Consensus clustering divided LN into two subtypes: subtype1, characterized by inflammation and immune activation, and subtype2, characterized by cellular metabolism. WGCNA highlighted the grey60 module linked to subtype1, and identified GBP2 and EIF2AK2 as hub genes. Cellular experiments showed that GBP2 and EIF2AK2 were upregulated in LPS-stimulated macrophages and glomerular endothelial cells, and their siRNA-mediated knockdown triggered a decline in pyroptosis-related marker expression, implying their possible role as therapeutic targets for modulating pyroptosis in LN. In conclusion, GBP2 and EIF2AK2 show potential as candidate molecules for targeted therapy in LN.