Identifying Crucial Genes Associated with Pyroptosis in Lupus Nephritis

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Lupus nephritis (LN) is a severe kidney disease driven by immune complex deposition and inflammation.
• Pyroptosis, a pro-inflammatory cell death pathway, is increasingly recognized as a key contributor to renal injury in LN.

Purpose of the Study:

• To identify critical pyroptosis-related genes involved in LN pathogenesis.
• To develop a diagnostic model and explore therapeutic targets for LN.

Main Methods:

• Analysis of GEO datasets for differentially expressed pyroptosis genes in LN kidney tissues.
• Development of a predictive model using univariate and LASSO regression.
• Consensus clustering to classify LN subtypes.
• Weighted gene co-expression network analysis (WGCNA) to identify key genes.
• Validation using Nephroseq, scRNA-seq, and cellular experiments.

Main Results:

• Identified 26 differentially expressed pyroptosis genes in LN glomeruli.
• Developed a 10-gene predictive model with high diagnostic accuracy (AUC > 0.968).
• Classified LN into two subtypes: inflammatory/immune-activated and metabolic.
• Identified GBP2 and EIF2AK2 as key hub genes associated with the inflammatory subtype.
• Validated GBP2 and EIF2AK2's role in pyroptosis and their upregulation in LN-relevant cells.

Conclusions:

• GBP2 and EIF2AK2 are significantly upregulated in LN and play a role in pyroptosis.
• These genes represent potential therapeutic targets for modulating pyroptosis in lupus nephritis.