Copper-Driven Epithelial Barrier Disruption: A Novel Mechanism of COPD Acute Exacerbations Mediated by the TNF-α/ATP7A Axis.

Elevated copper levels are associated with chronic obstructive pulmonary disease (COPD) and susceptibility to acute exacerbations of COPD (AECOPD), but the underlying mechanisms remain unclear. This study aimed to investigate the association between copper levels and AECOPD and elucidate the underlying mechanisms. A cross-sectional analysis of NHANES 2011-2012, a hospital-based case-control study enrolling 30 AECOPD patients and 30 healthy controls, and a one-year prospective follow-up of COPD patients demonstrated that higher serum copper levels were associated with more frequent exacerbations and earlier recurrence. Integrated studies using copper-manipulated COPD mice, zebrafish, lung organoids, and BEAS-2B cells, together with bulk and single-cell RNA sequencing, colorimetric copper quantification, ELISA-based tumor necrosis factor-α (TNF-α) measurement, oxidative stress and mitochondrial functional analyses, and FITC-dextran permeability assays, showed that excess copper induced mitochondrial oxidative stress, tight-junction loss, and epithelial barrier dysfunction. Mechanistic analyses revealed that TNF-α suppressed ATPase copper-transporting alpha (ATP7A) transcription through competition between NF-κB and CREB1 for the shared coactivator CBP, thereby promoting intracellular copper accumulation. ATP7A restoration alleviated epithelial injury, whereas ATP7A silencing abolished the improvement conferred by anti-TNF-α therapy in COPD mice. These findings identify the copper-TNF-α/ATP7A axis as a mechanism underlying AECOPD and a potential therapeutic target.