Airway epithelial dysfunction in asthma pathogenesis: epigenetic mechanisms, inflammatory crosstalk, and therapeutic opportunities.

Asthma affects over 260 million people worldwide and remains incompletely explained by the traditional T cell-centric immunological model, which offers incomplete mechanistic explanations for disease chronicity, recurrence during clinical remission, and the poor treatment response observed in T2-low phenotypes. Emerging evidence positions the airway epithelium as a central organizer of asthma pathogenesis rather than a passive barrier. This review proposes a unifying framework in which airway epithelial dysfunction and epigenetic memory drive the persistent and relapse-prone nature of asthmatic airways. We first examine how structural barrier defects-including tight junction dysfunction mediated by claudin-18 and E-cadherin loss-initiate and amplify type 2 inflammation through alarmin release (TSLP, IL-33, IL-25) and ILC2 activation. We then review how environmental exposures and inflammatory signals, particularly IL-13, induce durable epigenetic reprogramming of airway epithelial cells through DNA methylation, histone modifications, and non-coding RNAs, establishing molecular imprints that persist beyond the resolution of acute inflammation. Special attention is given to basal progenitor cells as repositories of allergic epigenetic memory, and to the concept of trained innate immunity as a mechanism underlying chronic airway hyperresponsiveness. We further contrast the epigenetic landscapes of T2-high and T2-low asthma, identifying the latter as a critical unmet need for biomarker and therapeutic development. Finally, we discuss translational opportunities, including HDAC inhibitors, miRNA-based therapies, and the potential of anti-alarmin biologics (tezepelumab, itepekimab) and downstream cytokine receptor antagonists (dupilumab) to partially restore epithelial function and progenitor states. We acknowledge that, given current data availability, this review is weighted toward T2-high (eosinophilic) endotypes; mechanistic characterization of T2-low asthma remains an important area for future investigation. This framework reconceptualizes asthma not only as a disorder of dysregulated immunity, but as a disease of maladaptively reprogrammed barrier tissue, with important implications for disease prevention, endotype-specific treatment, and the goal of achieving true biological remission.