UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis.

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality; however, its pathogenesis remains incompletely understood, limiting therapeutic options. Protein neddylation, a key post-translational modification, has been implicated in chronic inflammatory diseases, but its role in COPD remains largely unexplored. Therefore, this study aims to investigate the role of protein neddylation in the pathogenesis of COPD and to explore its potential as a novel therapeutic target. Methods: We assessed the neddylation pathway in macrophages from patients with COPD and from mice exposed to cigarette smoke (CS). Myeloid-specific ubiquitin-conjugating enzyme E2 M ( Results: Alveolar macrophages from COPD patients and CS-exposed mice exhibited significant downregulation of UBE2M. UBE2M-cKO was sufficient to induce spontaneous emphysema, characterized by increased lung volume, alveolar destruction, and impaired lung function, and it exacerbated CS-induced lung injury. This phenotype was specific to myeloid UBE2M-cKO, as neither CTF-UBE2M nor UBE2F-cKO recapitulated the disease. Transcriptomic profiling of UBE2M-cKO macrophages identified matrix metalloproteinase 12 ( Conclusion: Our study identifies UBE2M as a critical protector against emphysema by promoting HIF-2α degradation, thereby suppressing MMP12 expression. The UBE2M-HIF-2α-MMP12 axis represents a novel and specific pathogenic pathway in COPD, offering promising therapeutic targets.