Key Genes Associated with Pyroptosis in Gout and Construction of a miRNA-mRNA Regulatory Network.

Abstract

This study aimed to analyze key hub genes related to pyroptosis in gout and construct a miRNA-mRNA regulatory network using bioinformatic tools to elucidate the pathogenesis of gout and offer novel ideas to develop targeted therapeutic strategies for gout. Methods: The GSE160170 dataset was downloaded from the GEO database. The expression data extracted from the dataset were used to screen for differentially expressed genes (DEGs), which intersected with pyroptosis-related genes. These DEGs were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and a protein–protein interaction (PPI) network was constructed to identify pyroptosis-related hub DEGs. The relationship between upstream miRNAs and the hub genes was analyzed, miRNA-mRNA networks belonging to gout disease were constructed and samples from patients with gout were used for experimental verification. The CTDbase tool was used to analyze the identified hub genes and construct a molecular docking model. Results: A total of 943 DEGs (380 upregulated and 563 downregulated) were identified by analyzing the data of patients with early-stage gout and healthy control individuals in the GSE160170 dataset. DEGs and pyroptosis-related genes were intersected to obtain 17 pyroptosis-related DEGs associated with gout; of which, 12 were upregulated, and five were downregulated. The results of GO and KEGG analyses revealed that the DEGs were enriched in inflammatory and immune signaling pathways. Additionally, the DEGs were found to regulate inflammatory responses and were associated with apoptosis. TNF, IL-1β, NLRP3, CXCL8, PTGS2, NFE2L2, CASP8, and CD274 were identified as key hub genes in the PPI network, and a miRNA-mRNA network was constructed, which had 16 edges. Experimental validation revealed that PTGS2 and NFE2L2 were significantly upregulated, and CASP8 and CD274 were significantly downregulated in gout. In addition, miR-128-3p, miR-16-5p, miR-155-5p, and miR-20a-5p (associated with the miRNA-mRNA regulatory network) were significantly downregulated in gout. Five potential therapeutic drugs with stable PTGS2 binding were selected to develop a molecular docking model. Conclusion: A miRNA-mRNA potential regulatory network was constructed based on pyroptosis-related DEGs associated with gout. miR-16-5p, miR-128-3p, miR-20a-5p, and miR-155-5p can potentially influence pyroptosis and the occurrence and development of gout by affecting the expression of the PTGS2, CASP8, NFE2L2, and CD274 genes. Screening of celecoxib and resveratrol and other targeted drugs with stable binding. The findings of this study offer valuable insights into the regulatory mechanisms of gout and may help to identify Biomarkers and develop targeted therapeutic strategies for gout.