Targeted inhibition of m6A demethylase FTO by FB23 attenuates allergic inflammation in the airway epithelium

• Published in: The FASEB journal 2024-08, Vol.38 (15), p.e23846-n/a
• Main Authors: Lian, Zexuan, Chen, Ruchong, Xian, Mo, Huang, Peiying, Xu, Jiahan, Xiao, Xiaojun, Ning, Xiaoping, Zhao, Jin, Xie, Jianlei, Duan, Jielin, Li, Bizhou, Wang, Wanjun, Shi, Xu, Wang, Xinru, Jia, Nan, Chen, Xuepeng, Li, Jing, Yang, Zhaowei
• Format: Article
• Language: English
• Subjects: allergic inflammation; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Animals; asthma; Asthma - genetics; Asthma - metabolism; epithelial cells; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - drug effects; Female; FTO; Humans; Hypersensitivity - drug therapy; Hypersensitivity - metabolism; Inflammation - metabolism; m6A; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202400545R

Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity‐associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small‐molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO‐regulated transcriptome‐wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP‐seq) and RNA‐seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue‐specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL‐4/IL‐13‐treated epithelial cells and house dust mite (HDM)‐induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF‐α signaling via NF‐κB and epithelial–mesenchymal transition‐related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23‐induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM‐induced mice, potentially through diverse cellular processes and epithelial–mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management. The targeted inhibition of m6A demethylase FTO by a small‐molecule inhibitor FB23 reduces allergic inflammation both in vivo and in vitro, indicating its potential involvement in the NF‐κB and EMT signaling pathways. Moreover, FTO is extensively expressed across various cell types within the human bronchial mucosa, including epithelial cells, submucosal gland cells, and smooth muscle cells.