Identifying pyroptosis-related molecular subtypes in asthma through gene expression profiles: implications for airway inflammation

Background Asthma is a highly heterogeneous chronic respiratory disease, and accumulating evidence indicates a role for pyroptosis in its pathogenesis. However, few studies have identified pyroptosis-related asthma subtypes or systematically evaluated the role of pyroptosis-related genes (PRGs) in asthma. Methods We utilized GSE137268 to conduct Gene Set Variation Analysis (GSVA) to assess pyroptosis enrichment scores in patients with asthma compared to healthy controls. We then confirmed the differences in pyroptosis levels in murine asthma models. Next, we grouped asthma cases from the dataset using consensus clustering based on the PRG expression profiles. We used Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single sample Gene Set Enrichment Analysis (ssGSEA) to analyze the biological functions and immune status of each subgroup. We constructed a protein-protein interaction (PPI) network to identify hub genes within these subtypes, and subsequently validated these genes using an independent dataset, GSE45111. Receiver operating characteristic (ROC) curves were applied to assess the discriminatory capacity of hub genes. Results Asthma samples exhibited significantly higher pyroptosis enrichment scores than control samples. The expression of IL-1β, IL-18 and GSDMD-N was elevated in murine asthma models. We identified two pyroptosis-related asthma subtypes: Cluster 1 and Cluster 2. Cluster 1 exhibited heightened inflammation, manifesting as eosinophilic, neutrophilic, and mixed granulocytic phenotypes, while Cluster 2 was linked to paucigranulocytic asthma with reduced inflammation. Analyses of GO, KEGG, and ssGSEA revealed clear differences in biological functions and immune profiles between the two subtypes. The PPI network analysis identified five hub genes: IL1B , TLR2 , MMP9 , ICAM1 , and NLRP3 . Receiver operating characteristic (ROC) analyses further indicated the discriminative power of these five genes in distinguishing Cluster 1 from Cluster 2. Clustering analysis in GSE45111 produced results consistent with those from GSE137268. Conclusions Aberrant pyroptosis is associated with airway inflammation in asthma. The subtypes, identified based on PRG expression profiles, showed distinct clinical features, gene expression patterns, biological functions, and inflammatory profiles, suggesting a role for pyroptosis in asthma heterogeneity.