DCLK1 mediates airway epithelial barrier disruption through NF-κB activation in severe asthma

Severe asthma is characterized by epithelial barrier dysfunction, airway remodeling, and chronic inflammation. Doublecortin-like kinase 1 (DCLK1), a kinase initially identified as a cancer stem cell marker, has been linked to NF-κB-mediated inflammatory responses. However, its role in TGF-β-induced epithelial barrier disruption in severe asthma remains unclear. The expression of DCLK1 and junctional proteins was examined in bronchial epithelial tissue biopsies and air-liquid interface (ALI) cultures derived from patients with severe asthma and healthy controls. The role of DCLK1 was investigated in vitro using TGF-β-treated BEAS-2B cells and in vivo using ovalbumin (OVA)- and house dust mite (HDM)-induced murine asthma models. Global DCLK1 knockout mice were employed to assess epithelial integrity, airway remodeling, and inflammatory responses in murine asthma. DCLK1 expression was increased in bronchial epithelial cells from patients with severe asthma. DCLK1 siRNA reversed TGF-β-induced epithelial dysfunction by restoring E-cadherin expression and reducing fibronectin and N-cadherin levels in BEAS-2B cells. Moreover, DCLK1 silencing improved epithelial barrier function, as evidenced by increased transepithelial electrical resistance (TEER) and E-cadherin expression. Mechanistically, DCLK1 mediates TGF-β-induced EMT via activation of the NF-κB signaling pathway. DCLK1 knockout mice exhibited improved lung function and reduced airway inflammatory cell infiltration compared with wild-type mice under both OVA and HDM exposure. DCLK1 promotes airway epithelial barrier dysfunction in severe asthma through NF-κB activation. Targeting DCLK1 may represent a novel therapeutic strategy to restore epithelial integrity in severe asthma.