{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:54:59Z","timestamp":1790794499715,"version":"4.1.0"},"reference-count":73,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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\u2010sectional analysis of NHANES 2011\u20132012, a hospital\u2010based case\u2010control study enrolling 30 AECOPD patients and 30 healthy controls, and a one\u2010year prospective follow\u2010up of COPD patients demonstrated that higher serum copper levels were associated with more frequent exacerbations and earlier recurrence. Integrated studies using copper\u2010manipulated COPD mice, zebrafish, lung organoids, and BEAS\u20102B cells, together with bulk and single\u2010cell RNA sequencing, colorimetric copper quantification, ELISA\u2010based tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) measurement, oxidative stress and mitochondrial functional analyses, and FITC\u2010dextran permeability assays, showed that excess copper induced mitochondrial oxidative stress, tight\u2010junction loss, and epithelial barrier dysfunction. Mechanistic analyses revealed that TNF\u2010\u03b1 suppressed ATPase copper\u2010transporting alpha (ATP7A) transcription through competition between NF\u2010\u03baB 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\u2010TNF\u2010\u03b1 therapy in COPD mice. These findings identify the copper\u2013TNF\u2010\u03b1\/ATP7A axis as a mechanism underlying AECOPD and a potential therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.202519533","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Copper\u2010Driven Epithelial Barrier Disruption: A Novel Mechanism of COPD Acute Exacerbations Mediated by the TNF\u2010\u03b1\/ATP7A Axis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7149-2990","authenticated-orcid":false,"given":"Xinru","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine The Second People's Hospital of Changzhou The Third Affiliated Hospital of Nanjing Medical University  Changzhou 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