YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4 signaling

作者：Cancan Xie, Junwen Huang, Ying Chen, Bing Huang, Yaoxin Chen, Yuemao Li, Zhaoqian Gong, Yanyan Ma, Maosheng Xu, Keke Fan, Dapeng Hu, Xueying Zhao, Peng Huang, Xianru Peng, Shaoxi Cai, Wenqu Zhao, Haijin Zhao · 发表于：International Immunopharmacology · 年份：2025 · DOI：10.1016/j.intimp.2025.115181 · 被引用次数：6 · 研究领域：RNA modifications and cancer、Peptidase Inhibition and Analysis、Cancer-related gene regulation

BACKGROUND: Although N6-methyladenosine (m6A) modification and its reader protein YTHDF1 have been implicated in allergic airway inflammation, their roles in TDI-induced steroid-insensitive asthma remains unclear. β-catenin signaling is vital for airway inflammation and mitochondrial function in asthma. In this study, we investigated the interplay between β-catenin/TCF4 signaling and m6A-dependent regulation in a TDI-induced asthma model (TDI-AM). METHOD: Mice were sensitized and challenged with TDI or house dust mite (HDM) to establish asthma models. Mice were administered the YHTDF1 m6A modification inhibitor (Tegaserod), the β-catenin/TCF4 signaling inhibitor (LF3), and the mitochondrial stabilizing drug SS-31 triacetate. Human serum albumin-containing TDI was introduced to human bronchial epithelial cells and macrophages to mimic the asthma model. RESULT: YTHDF1 was upregulated in the TDI-AM. Pretreatment with a 1 mg/kg concentration of Tegaserod in TDI-AM revealed significant alleviation of TDI-induced airway hyperresponsiveness, airway inflammation, airway remodeling, and mitochondrial dysfunction, but pretreatment with 5 mg/kg concentration of Tegaserod showed the opposite effect. The changes above corroborated in HDM-induced asthmatic mice. JASPAR software predicted the β-catenin signaling downstream transcription factor TCF4 combined with YTHDF1 promoter region, suggesting a possible interaction between TCF4 and YTHDF1. Blockade of β-catenin/TCF4 signaling with LF3 l...