Transcriptomic and Functional Responses of Human Airway Cells to Vaped ∆8-THC and its Oxidation Product ∆8-THCQ

Δ8tetrahydrocannabinol (Δ8THC) products have expanded rapidly since the 2018 Farm Bill, yet they remain largely unregulated despite containing high cannabinoid levels, additives, and contaminants, and growing evidence of respiratory risks. We identify the reactive electrophile Δ8THC quinone (Δ8THCQ, HU336) as a major constituent of commercial Δ8THC distillates and disposable vape products, with concentrations increasing substantially after vaping. Across highpotency products, Δ8THCQ rose an average of 3.67fold, reaching millimolar levels. While Δ8THC alone elicited no detectable transcriptomic response in a bronchial epithelial cell line, Δ8THCQ caused marked geneexpression changes, activating ciliarelated, stressresponse, xenobioticmetabolism, and inflammatory pathways. Using primary differentiated human bronchial epithelial cells and the UNC Vaping Product Exposure System (VaPES), we found that aerosols from commercial Δ8THC mixtures rapidly induced immediateearly stress genes, suppressed ribosomal and mitochondrial programs, and activated fibrosislinked signaling. In contrast, Δ8THCcontaining “juice” products had milder effects, mainly upregulating cellcycle and proliferation pathways. Computational analyses linked the chemical composition of Δ8THC aerosols to distinct transcriptional responses, identifying clusters of compounds driving specific airway effects. Functionally, distillate and disposable aerosols impaired motilecilia activity. Collectively, these findings indicate that vaping generates substantial Δ8THCQ and suggest that repeated inhalation may disrupt mucociliary defense and promote chronic airway injury.