Epigenetic regulation of airway epithelial barrier dysfunction in pediatric asthma: mechanistic insights and therapeutic potential

Pediatric asthma, a chronic respiratory disorder characterized by airway inflammation and remodeling, is increasingly linked to epigenetic dysregulation of the airway epithelial barrier. This review explores how DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) impair epithelial integrity, amplify immune responses, and sustain chronic inflammation and tissue remodeling. Aberrant methylation of barrier-related genes (FLGs, CLDNs) disrupts tight junctions and enhances allergen penetration. Methylation abnormalities of immune regulators (IL-13, ALOX12) drive Th2-mediated inflammation, with environmental pollutants such as PM2.5 exacerbating these changes. Elevated H3K27me3 levels and histone deacetylase (HDAC) overactivation suppress immune tolerance genes (e.g., IL-4) and compromise junctional proteins (e.g., occludin), whereas HDAC inhibitors demonstrate preclinical efficacy in restoring barrier function. Dysregulated ncRNAs, such as miR-21 and miR-146, modulate inflammatory pathways, with miR-146a mimics reducing eosinophilic inflammation via NF-κB inhibition. Clinically, epigenetic biomarkers such as ALOX12 hypomethylation have diagnostic potential for asthma phenotypes. Emerging therapies, including DNA methyltransferase inhibitors (5-azacytidine) and HDAC inhibitors (vorinostat), show promise but face challenges such as limited clinical validation and discrepancies between animal models and human disease. Future priorities involve integrating multi-omics approaches to unravel the complexity of asthma, optimizing non-invasive biomarker detection, and developing personalized therapies tailored to epigenetic profiles. By bridging mechanistic insights with clinical innovations, epigenetic strategies may revolutionize precision medicine in pediatric asthma management.