Histone Lactylation Enhances Th17 Cell Differentiation Through DPP4 to Promote Epithelial-Mesenchymal Transition in Asthma

The airway remodeling in asthma is closely associated with the abnormal differentiation of Th17 cells and epithelial-mesenchymal transition (EMT) of bronchial epithelial cells. This study aims to elucidate the regulatory mechanisms of histone lactylation in Th17 cell differentiation and the EMT of bronchial epithelial cells. An asthma mouse model was constructed, pathological changes, immune cell subsets, and histone lactylation levels were analyzed. CD4⁺ T cells from normal and asthmatic mice were treated with a glycolysis activator (Nala) or inhibitor (2-deoxy-glucose (2-DG)). ChIP-qPCR and dual-luciferase assay were performed to verify the regulation of DPP4 promoter by H3K18la. DPP4 inhibitor (K579) was used to intervene in Th17 cell differentiation. Finally, bronchial epithelial cells were induced to undergo EMT by TGF-β1, and co-cultured with CD4 + T cells to evaluate EMT markers. The asthma mouse model showed lung inflammation, airway remodeling, and imbalance in immune cell subsets. H3K18la and DPP4 levels were upregulated, correlating positively with IL-17. Inhibiting glycolysis reduced H3K18la, inhibited Th17 cell differentiation, and decreased IL-17 secretion. H3K18la activated DPP4 transcription by enriching in DPP4 promoter region. K579 blocked Th17 cell differentiation mediated by H3K18la. Additionally, DPP4 significantly promoted the EMT of bronchial epithelial cells by promoting Th17 cell differentiation, as evidenced by downregulation of E-cadherin, upregulation of α-SMA, and changes in cell morphology. This process was partially inhibited by 2-DG treatment. H3K18la promoted Th17 cell differentiation by activating DPP4, thereby driving the EMT of bronchial epithelial cells. Targeting H3K18la-DPP4-Th17 axis may be a potential asthma therapy. H3K18la promoted Th17 cell differentiation by activating DPP4, thereby driving the EMT of bronchial epithelial cells. Additionally, DPP4 significantly promoted the EMT of bronchial epithelial cells through promoting Th17 cell differentiation