Epithelial Fucosylation Drives Airway Barrier Dysfunction and Allergic Inflammation via a FUT1 ‐CDH12 Axis

BACKGROUND: Airway epithelial barrier dysfunction is a central feature of asthma pathogenesis, yet the molecular mechanisms by which post-translational modifications regulate epithelial integrity remain incompletely understood. Fucosylation has emerged as a potential regulator of epithelial homeostasis across mucosal tissues. OBJECTIVE: We sought to investigate whether epithelial fucosylation contributes to allergen-induced barrier dysfunction and airway inflammation and to define their underlying mechanisms. METHODS: Fucosylation levels were assessed in saliva from children with asthma using mass spectrometry. Air-liquid interface epithelial cultures were used to assess barrier function by transepithelial electrical resistance, tight junction protein expression and cytokine release. Transcriptomic analyses were performed to identify dysregulated fucosylation pathways. Fut1 was selectively inhibited in vivo and in vitro using intratracheally delivered AAV6-encoded shRNA. Downstream targets were also evaluated by RNA sequencing. RESULTS: Fucosylation was significantly increased in saliva from children with asthma and in allergen-exposed mouse airways. Pharmacologic inhibition of fucosylation preserved epithelial barrier integrity, maintained junctional organization and reduced allergen-induced epithelial cytokine release. Transcriptomic profiling identified fucosylation as a major upregulated pathway, with increased expression of Fut1, Fut2, Fut7 and Fut9. Epithelial-specific Fut1 knockdown attenuated Th2-driven inflammation, preserved epithelial junctional architecture and suppressed alarmin release. Integrated analyses revealed 56 Fut1-dependent genes enriched in cell-adhesion pathways, including Cdh12, App, Ank3 and Cd9. Fut1-CDH12 protein interaction was confirmed by immunoprecipitation, and FUT1-dependent induction of CDH12 disrupted epithelial junctional organization and barrier function. CONCLUSION: These findings identify the FUT1-CDH12 axis as a previously unrecognized epithelial mechanism promoting barrier dysfunction and allergic airway inflammation in asthma.