NOD1 modulates chronic obstructive pulmonary disease progression via FOXA1/NLRP3-mediated regulation of pyroptosis.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation. In this study, we established cellular models of COPD using bronchial epithelial cells and also constructed animal models to verify the protective effect of NOD1 knockout on lung tissue in COPD model mice, aiming to elucidate the molecular events linking increased NOD1 expression to inflammatory cell death. Transcriptomic and functional analyses revealed that NOD1 promotes pyroptosis in COPD via the FOXA1-NLRP3 signaling axis, with the PI3K-Akt pathway mediating these effects. Mechanistically, NOD1 suppresses FOXA1, leading to upregulation of NLRP3 and enhanced release of pro-inflammatory cytokines IL-18 and IL-1β. Knockdown of NOD1 alleviated pyroptosis and improved cell survival, effects reversed by NLRP3 overexpression. In conclusion, our findings identify the NOD1-FOXA1-NLRP3 axis as a key driver of inflammatory cell death in COPD, advancing our understanding of disease pathogenesis and highlighting potential molecular targets for therapeutic intervention.