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Once polarized, the airway epithelium functions as a barrier against opportunistic pathogens. Yet, the mechanisms that temporally regulate polarization, a process which is disrupted in cystic fibrosis (CF), remain unclear. Here, we demonstrate the functional importance of connexin 43 (Cx43), a gap junction protein, which is normally repressed during regeneration of the airway epithelium. We show that prolonged post-transcriptional stabilization of Cx43 leads to altered collective cell orientation and compromised CF airway epithelial barrier. We report a bidirectional cooperation between Cx43 hemichannel function and adenosine signaling in disrupting ER-Golgi secretory axis, cytoskeleton dynamic and ectopic apical fibronectin production. Genetic and pharmacological inhibition of Cx43 channels re-established polarity and spatial organization of CF airway epithelial cells. Finally, targeting Cx43 hemichannels with mimetic peptides normalizes the CF-dependent fibronectin ectopic expression and prevents the enhanced\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    trapping to the CF epithelium. Our findings reveal a mechanism in which temporally controlled Cx43-mediated intercellular communication is crucial for coordinating intrinsic polarity programs and maintaining airway epithelium integrity.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10413-7","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T13:05:59Z","timestamp":1781269559000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cx43 levels guide apicobasal polarity in regenerating airway epithelial cells"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5139-9304","authenticated-orcid":false,"given":"Mehdi","family":"Badaoui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Luscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1950-0144","authenticated-orcid":false,"given":"Mengjie","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Bacchetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"van Delden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4889-9492","authenticated-orcid":false,"given":"Thilo","family":"K\u00f6hler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-6134","authenticated-orcid":false,"given":"Arantxa","family":"Tabernero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-2090","authenticated-orcid":false,"given":"Marc","family":"Chanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"10413_CR1","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/s41580-022-00465-y","volume":"23","author":"CE Buckley","year":"2022","unstructured":"Buckley, C. 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