Abstract

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 ( Ube2m ) knockout (UBE2M-conditional knockout [cKO]) mice were generated to investigate the causal role of UBE2M in emphysema. Cell-type specificity was confirmed using club cell-specific knockout (CTF-UBE2M) and myeloid-specific ubiquitin-conjugating enzyme E2 F ( Ube2f ) knockout (UBE2F-cKO) mice. Transcriptomic profiling, molecular biology techniques, and pharmacological inhibition were employed to delineate the underlying mechanisms. 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, as neither CTF-UBE2M nor UBE2F-cKO recapitulated the disease. Transcriptomic profiling of UBE2M-cKO macrophages identified matrix metalloproteinase 12 ( Mmp12 ) as a key mediator of the emphysema phenotype, given its macrophage-specific expression and potent elastin-degrading function. Mechanistically, UBE2M deficiency led to the stabilization of hypoxia-inducible factor-2α (HIF-2α, encoded by Epas1 ), a known neddylation substrate, resulting in transcriptional upregulation of Mmp12 . The HIF-2α inhibitor