Convergent death programs in chronic obstructive pulmonary disease: how pyroptotic and ferroptotic crosstalk reshapes...

Chronic obstructive pulmonary disease (COPD) remains a leading cause of global mortality, yet current therapies principally target bronchodilation and broad anti-inflammatory suppression rather than the regulated cell death programs driving tissue destruction. Pyroptosis, executed through inflammasome-driven gasdermin pore formation, and ferroptosis, mediated by iron-catalyzed lipid peroxidation upon GPX4 failure, have each been implicated in COPD pathogenesis but are conventionally treated as independent processes. This review advances three original contributions. First, we map pyroptotic and ferroptotic associations across COPD inflammatory endotypes, demonstrating preferential non-canonical pyroptotic engagement in T2-low neutrophilic disease and dual death-modality involvement in T2-high eosinophilic disease. Second, we delineate a hierarchical relationship-now supported in COPD-relevant epithelial systems-in which smoke-induced Nrf2 epigenetic silencing drives ferroptotic lipid peroxide accumulation that directly triggers pyroptotic execution through caspase-11 activation, positioning GPX4 as the molecular gatekeeper. Third, we propose an inverted U-shaped model reconciling paradoxical effects of lipid peroxidation on inflammasome regulation, where membrane phospholipid hydroperoxides drive activation while free cytosolic 4-hydroxynonenal mediates suppression through covalent NLRP3 modification. We further integrate extracellular trap biology as a convergent death-associated program sharing execution machinery with pyroptosis and ferroptosis. Building on this framework, we critically appraise emerging therapeutics-including dupilumab, anti-alarmin biologics, NLRP3 inhibitors, and ferroptosis-directed agents-and propose a biomarker-guided precision medicine strategy matching cell death-targeting therapies to individual inflammatory profiles. This framework reframes COPD therapeutic design from single-pathway inhibition toward integrated modulation of interconnected death programs stratified by inflammatory endotype.