JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodelling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Using a patient-derived 3D distal airway epithelial organoid model, we successfully recapitulate important IPF features, including the emergence of aberrant KRT5+/COL1A1+ basal cells and a metabolic shift towards increased O-linked {beta}-N-acetylglucosamine (O-GlcNAc) levels. Consistent with this, single-cell analysis of accessible chromatin reveals an increased chromatin accessibility in these aberrant basal cells, particularly at JUNB motif-enriched promoter regions of metabolic genes. O-GlcNAcylation shapes JUNB function and promotes a pro-fibrotic response to chronic injury, leading to aberrant epithelial remodelling. Site-specific deletion of O-GlcNAcylation on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, these data establish a novel link between metabolic dysregulation, mediated by the O-GlcNAc-JUNB axis, and bronchiolization in IPF, offering new therapeutic strategies to treat this fatal disease.