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E-cadherin, a key adherens junction protein required for epithelial cohesion, can undergo proteolytic cleavage to generate soluble E-cadherin (sE-cad), a mediator of epithelial barrier dysfunction and inflammation. We hypothesized that e-cigarette aerosol exposure promotes MMP-dependent E-cadherin cleavage, resulting in sE-cad release and epithelial barrier disruption. Using differentiated primary normal human bronchial epithelial (NHBE) cells, 16HBE cells, and a murine whole-body exposure model, we examined epithelial injury induced by physiologically relevant aerosols generated with a programmable puffing system. Air Factory salt e-liquid was used at 18\u00a0mg\/mL nicotine for in vitro studies and 36\u00a0mg\/mL for in vivo exposures. Immunoblotting demonstrated increased sE-cad levels in apical supernatants and bronchoalveolar lavage fluid. Aerosol exposure upregulated MMP-2, MMP-9, and MMP-12 expression. E-cigarette aerosol exposure significantly reduced transepithelial electrical resistance, increased FITC-dextran permeability, and disrupted airway epithelial barrier structure, indicating impaired barrier integrity and function. These effects were attenuated by pretreatment with the MMP inhibitor fisetin, which preserved barrier function and junctional protein localization. Fisetin treatment significantly reduced e-cigarette\u2013induced sE-cad release and was associated with a marked reduction in MMP-9 expression, whereas MMP-2 and MMP-12 levels were not altered, identifying MMP-9 as a key mediator of E-cadherin cleavage. Collectively, these findings establish MMP-dependent E-cadherin cleavage as a mechanistic driver of e-cigarette\u2013induced epithelial barrier dysfunction and identify sE-cad as a potential early biomarker and therapeutic target for aerosol-induced airway injury.<\/jats:p>","DOI":"10.1007\/s00204-026-04456-2","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T12:27:40Z","timestamp":1780662460000},"page":"4667-4680","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Electronic cigarette aerosols disrupt airway barrier function via MMP-dependent E-cadherin cleavage: findings from cell culture and murine models"],"prefix":"10.1007","volume":"100","author":[{"given":"Amelia L.","family":"Beaumont","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah G.","family":"Ozeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Chatburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P.","family":"Bowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7625-3341","authenticated-orcid":false,"given":"Fariba","family":"Rezaee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"4456_CR1","doi-asserted-by":"publisher","first-page":"108846","DOI":"10.1016\/j.cbi.2019.108846","volume":"314","author":"H Agraval","year":"2019","unstructured":"Agraval H, Yadav UCS (2019) MMP-2 and MMP-9 mediate cigarette smoke extract-induced epithelial-mesenchymal transition in airway epithelial cells via EGFR\/Akt\/GSK3beta\/beta-catenin pathway: amelioration by fisetin. 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