Childhood asthma remains a global public health challenge with suboptimal control, despite the availability of inhaled corticosteroids (ICS) as first-line therapy. Glucocorticoids suppress inflammation and protect the airway epithelial barrier (AEB) via genomic and nongenomic pathways. However, a significant subset of patients, particularly those with severe asthma, exhibits glucocorticoid resistance. Emerging evidence reveals a dual role of glucocorticoids on the AEB: beyond protection, they may inadvertently compromise barrier integrity by inducing epithelial apoptosis and dysfunction. This review synthesizes current knowledge on glucocorticoid mechanisms in asthma, focusing on the AEB as a critical interface between therapeutic efficacy and treatment failure. We show that AEB impairment serves as one of the key mechanisms underpinning glucocorticoid resistance and the progression to severe asthma, with heightened relevance in children due to the unique vulnerability of their developing airways. Furthermore, we examine how infections, nutritional factors (e.g., vitamins A and D), and immune maturation intersect with AEB integrity and glucocorticoid responsiveness. By reframing the AEB as both a target and a determinant of glucocorticoid efficacy, this review highlights the urgent need for barrier-focused strategies to overcome resistance and improve outcomes in childhood asthma.
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