Peng Lu, Xing Li, Zhuying Li
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.