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

Purpose Asthma is a heterogeneous condition and emerging studies suggest a link between pyroptosis and the disease's development. However, few studies have identified pyroptosis-related asthma subtypes and thoroughly evaluated the role of pyroptosis-related genes (PRGs) in asthma. Methods We utilized the GSE137268 to conduct gene set variation analysis (GSVA) assessing pyroptosis levels in asthma. We then verified the pyroptosis level differences in murine asthma models. Next, we grouped asthma cases from the dataset using consensus clustering based on PRGs. 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 the identified subtypes, and subsequently validated the identified subtypes using an independent dataset, GSE 45111. Results Asthma samples exhibited higher pyroptosis enrichment scores than control samples. The expression of IL-1β, IL-18 and GSDMD-N increased in asthma murine models. We identified two pyroptosis-related asthma subtypes: Cluster 1 and Cluster 2. Cluster 1 showed elevated inflammation, characterized by eosinophilic, neutrophilic, and mixed granulocytic asthma, 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) analysis further indicated discriminative power of these five genes to differentiate between Cluster 1 and Cluster 2. Notably, the clustering analysis applied to the GSE 45111 yielded results consistent with the subtypes identified in GSE 137268. Conclusion Aberrant pyroptosis is found in asthma and linked to airway inflammation. The subtypes identified through their PRGs expression profiles showed distinct clinical features, gene expression patterns, biological functions and inflammatory statuses.