We have delineated a cohesive model wherein distinct pyroptotic pathways drive specific asthma endotypes: allergen-driven, NLRP3-GSDMD/GSDME-mediated circuits predominantly fuel the type 2 inflammation and remodeling of Th2-high/eosinophilic asthma, whereas pollutant- and virus-activated, non-canonical caspase-4/5-AIM2 axes propel the neutrophilic inflammation and steroid resistance characteristic of Th2-low asthma. The gene discussed is GSDME; the disease is asthma.