Epithelial AhR Suppresses Allergen-Induced Oxidative Stress and Senescence via c-Myc Regulation

Environmental allergens trigger epithelial reactive oxygen species (ROS) production and cellular senescence, contributing to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may modulate this process. Single-cell transcriptomics from allergen-challenged bronchoalveolar brushings of allergic asthma and non-asthmatic allergic control subjects were analyzed for ROS, senescence, and AhR activity. Club cell-specific p16 knockout (<i>p16^ΔScgb1a1</i>) and AhR-deficient (<i>AhR^ΔScgb1a1</i>) mice were used to assess epithelial senescence and AhR function. Single-cell analysis revealed epithelial senescence as a hallmark of allergen-induced asthma. <i>p16^ΔScgb1a1</i> mice exhibited reduced ROS levels and airway inflammation. Single-cell analysis also demonstrated increased AhR activity and ROS generation in airway epithelial cells of allergen-treated asthmatics, and ROS correlated positively with AhR activity and senescence. It was documented that the regulation of AhR on senescence was attenuated by VAF347, whereas AhR deficiency exacerbated ROS generation and inflammation in <i>AhR^ΔScgb1a1</i> mice. RNA-seq identified senescence as a key AhR-regulated pathway, implicating c-Myc, TGF-β2, and SERPINE1 as major targets. AhR binding to the c-Myc promoter was confirmed by ChIP-PCR, and pharmacologic inhibition of c-Myc with EN4 reduced allergen-induced ROS, senescence, and inflammation. These findings demonstrate that epithelial AhR suppresses allergen-induced ROS generation and cellular senescence via direct regulation of c-Myc.