ZBP1 is a significant pyroptosis regulator for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a common autoimmune disease that affects all organs. Recently, several studies have shown that pyroptosis playsa significant process in the occurrence and progression of SLE. However, no study has investigated the association between pyroptosis genes and SLE. We conducted this study to examine this association.

The GSE11090, GSE20864, and GSE112087 gene microarrays of normal and SLE patient samples were downloaded from the Gene Expression Omnibus database. A differentially expressed gene (DEG) analysis was performed using the LIMMA package in R software. Log₂ fold change |log_FC| >0.5 and a false discovery rate (FDR) <0.05 setting for DEGs' screening value. We also performed an enrichment function analysis of the DEGs. To explore the role of pyroptosis genes in SLE, we selected pyroptosis genes that intersected with the DEGs for further analysis, we also examined the expression levels of the selected genes, their association with immune cell infiltration, and conducted western blotting and polymerase chain reaction analyses to confirm the selected genes expression levels in the SLE and normal samples.

A total of 3,398 identical genes were obtained from 3 datasets for the differential analysis. 84 upregulated genes and 52 downregulated genes were identified in SLE. The enrichment function analysis revealed that DEGs act as key regulators of nicotinamide adenine dinucleotide (NADH) dehydrogenase activity, phospholipid scramblase activity, double-stranded ribonucleic acid (RNA) binding, and the interferon signaling pathway. We identified the SLE-related pyroptosis gene, Z-DNA binding protein 1 (ZBP1), by intersecting the DEGs of SLE and 40 pyroptosis genes. The differential analysis indicated that ZBP1 was more highly expressed in SLE patients compared to normal samples (P<0.001). Additionally, the expression of ZBP1 was higher in females than males (P=0.008). The SLE samples had different immune cell infiltration than the normal samples, and ZBP1 was significantly correlated with immune cell infiltration in the SLE samples. Finally, the validation experiments results showed that ZBP1 expression levels were significantly more highly expressed in female and SLE patients, than male and normal patients.

ZBP1 may indicate that females have a high incidence rate of SLE, and it plays a significant role in the occurrence and progression of SLE.