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

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

  • Int Immunopharmacol. 2025 Sep 23:162:115181. doi: 10.1016/j.intimp.2025.115181.
Cancan Xie 1,  Junwen Huang 2,  Ying Chen 2,  Bing Huang 3,  Yaoxin Chen 2,  Yuemao Li 4,  Zhaoqian Gong 2,  Yanyan Ma 2,  Maosheng Xu 2,  Keke Fan 2,  Dapeng Hu 2,  Xueying Zhao 2,  Peng Huang 3,  Xianru Peng 5,  Shaoxi Cai 2,  Wenqu Zhao 6,  Haijin Zhao 7
Affiliations

Affiliations

  • 1 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China; Department of Critical Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 412007, China.
  • 2 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China.
  • 3 Department of Critical Care Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 412007, China.
  • 4 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 6 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China. Electronic address: 398535173@qq.com.
  • 7 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangdong 510515, China. Electronic address: zhjin@smu.edu.cn.
PMID: 40633209 DOI: 10.1016/j.intimp.2025.115181
Abstract

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 largely inhibited airway inflammation, mitochondrial dysfunction, and the expression of YTHDF1 in the TDI-AM. Treatment with LF3 can significantly inhibit the expression of YTHDF1 protein. The TDI-induced airway inflammation, as well as mitochondrial dysfunction, were both significantly decreased after treatment with SS-31 triacetate.

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

Keywords

Asthma; Mitochondrial dysfunction; Toluene diisocyanate; YTHDF1; m6A methylation modification; β-Catenin/TCF4.

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