Pyroptosis-related gene signature in neutrophils for predicting the prognosis of sepsis

Abstract

Abstract Background Sepsis is a systemic inflammatory response syndrome caused by pathogen infection, which is associated with pyroptosis. Previous studies have shown that neutrophil pyroptosis may play an important role in sepsis; however, the potential prognostic and diagnostic value of pyroptosis-related genes in sepsis remains undefined. Methods The RNA-seq data and clinical data of sepsis were extracted from the Gene Expression Omnibus (GEO) database. Then, neutrophil-related pyroptosis genes (NRPGs) were filtered by overlapping neutrophil-related genes obtained from weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) between sepsis and healthy samples and pyroptosis-related genes (PRGs) retrieved from prior reviews. Subsequently, survival analysis was performed, and the correlation between the NRPGs and clinical traits was assessed. Furthermore, independent prognostic indicators were screened using Cox regression analyses, and independent prognostic genes were defined as biomarkers. Gene set enrichment analysis (GSEA) was performed to explore the potential biological pathway related to biomarkers. Correlation between prognostic indicators and immune cell infiltration were investigated. Eventually, the potential therapeutic drugs targeting biomarkers were predicted from ZINC15 database. Results A total of 6 NRPGs were filtered by overlapping 3109 neutrophil-related module genes, 4078 DEGs, and 33 PRGs. Meanwhile, 5 NRPGs (CASP6, GSDMB, CASP4, ELANE, and NLRP3) were related to the survival of sepsis. The correlation analysis results indicated that CASP6, GSDMB, CASP4, ELANE, and NLRP3 were significantly correlated with endotype class. In addition, the age, endotype class, and ELANE were regarded as independent prognostic indicators, and ELANE could be used as a biomarker. GSEA suggested that ELANE was markedly related to endocytosis, bacterial infection, autophagy, cell cycle and TNF signaling pathway. Additionally, NK cell, myeloid dendritic cell, and neutrophil were different in ELANE expression groups, and NK cells and neutrophil had a strongly negative correlation with ELANE. Ultimately, molecular docking results showed ZINC000164760756 had the lowest docking energy, which might be used to treat sepsis by targeting ELANE. Conclusion ELANE may be used as a biomarker for sepsis, which may provide a theoretical basis for the investigation of the molecular mechanisms of sepsis.