Emerging roles of the gasdermin family in asthma

Asthma is a chronic and heterogeneous airway disease resulting from a complex interplay among genetic predisposition, environmental exposures, and immune dysregulation. Current therapies, including inhaled corticosteroids and biologics, provide symptom relief; however, many patients, particularly those with steroid-resistant or non-Th2 endotypes, do not achieve adequate control. Recent studies suggest that the gasdermin (GSDM) family—pore-forming proteins that mediate pyroptosis—play a role in asthma pathogenesis. Among them, GSDMB, GSDMA, and GSDMD contribute to distinct pathological mechanisms: GSDMB is implicated in epithelial pyroptosis, barrier disruption, and airway remodeling, while GSDMD mediates immune cell–driven inflammation by releasing pro-inflammatory cytokines. Although GSDM expression is partly determined by genetic polymorphisms, it is also dynamically regulated by inflammatory cytokines and environmental triggers such as allergens and pollutants. GSDMA is strongly associated with childhood-onset asthma, and its expression in epithelial cells is affected by asthma-related single nucleotide polymorphisms. Notably, polymorphisms in the GSDMB gene at the 17q21 locus are strongly associated with childhood-onset asthma, and isoform-specific functions influence epithelial damage and disease progression. These findings support a pathogenic model in which GSDM activity drives Th2 inflammation, airway remodeling, and disease chronicity. Targeting GSDM-mediated pathways may provide novel treatment options for patients unresponsive to standard therapies. Moreover, genotyping of GSDM variants could inform patient stratification in precision medicine. Future research should investigate the nonpyroptotic roles of GSDMs, isoform-specific mechanisms, and their potential as drug targets to advance the development of innovative asthma therapies.