PANoptosis in acute asthma exacerbation: Identification of key genes and immune dysregulation

Asthma, a chronic inflammatory disorder, imposes significant economic and social burdens despite advances in understanding its pathophysiology. PANoptosis, a newly identified form of programmed cell death involving pyroptosis, apoptosis, and necroptosis, has been linked to various respiratory diseases, but its role in asthma exacerbation remains unclear. This study aimed to investigate PANoptosis variations in asthma induced by different stimuli and identify potential therapeutic targets during acute asthma exacerbations. We generated a murine ovalbumin (OVA)-induced asthma model and subsequently challenged the mice with LPS or Poly(I:C) to assess the impact on airway inflammation. Results showed that LPS and Poly(I:C) significantly exacerbated PANoptosis in asthma models, with elevated levels of phospho-MLKL, NLRP3, and cleaved Caspase-3 and their colocalization. We retrieved asthma exacerbation-related dataset GSE256534 from the GEO database and identified 68 PANoptosis-associated differentially expressed genes (DEGs), including key genes CASP1 and CASP8. Functional enrichment analysis revealed their involvement in inflammation and immune response pathways. Immune cell infiltration analysis showed significant correlations between key genes and infiltrating immune cells. Validation in murine asthma models confirmed elevated Caspase-1 and Caspase-8 expression in OVA-induced asthma, further increased by LPS and Poly(I:C). Our study provides novel insights into PANoptosis in asthma exacerbation, highlighting the aggravating role of LPS and Poly(I:C). The identification of key genes such as CASP1 and CASP8 suggests potential therapeutic targets for managing acute asthma exacerbations.