Pyroptosis in chronic obstructive pulmonary disease: Beyond the canonical NLRP3/Caspase-1/GSDMD pathway.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is characterized by persistent airway inflammation that remains incompletely controlled in some patients despite current anti-inflammatory therapies. Pyroptosis, a pro-inflammatory, lytic form of programmed cell death mediated by the gasdermin family of proteins, has emerged as a key amplifier of inflammation in COPD. Although most evidence centers on the NLR family pyrin domain-containing 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) axis, COPD-relevant studies increasingly implicate non-canonical caspase-4/5/11-GSDMD signaling and alternative gasdermins. The evidence is hierarchical: GSDMD has the strongest cleavage-dependent support; gasdermin E (GSDME)-associated signaling has been linked experimentally to epithelial injury, whereas gasdermin C (GSDMC) and gasdermin B (GSDMB) are supported mainly by expression and stimulus-response data. We propose a "dual pyroptosis strike" model in which infection-associated non-canonical signaling may amplify a smoke-conditioned canonical background during acute exacerbations of COPD (AECOPD), while emphasizing that clinical execution-level validation remains lacking. This review synthesizes current findings into a conceptual gasdermin atlas, critically appraises cell-type- and disease-stage-specific findings, and discusses both therapeutic strategies and biomarker-guided approaches. Cleavage-resolved, cell-type-resolved, and longitudinal validation will be required before these pathways can inform patient stratification or targeted intervention.