2. Academic Validation
  3. Downregulation of METTL3 enhances TRADD-mediated apoptosis in inflammatory bowel disease

Downregulation of METTL3 enhances TRADD-mediated apoptosis in inflammatory bowel disease

  • Sci China Life Sci. 2025 Jul;68(7):2010-2027. doi: 10.1007/s11427-024-2799-6.
Tingyue Gong # 1,  Zhiyang Zeng # 2 3,  Zurui Huang # 4 5,  Yang Luo # 1,  Xiya Cao 3,  Hao Li 1,  Yongheng Zhao 1,  Dali Han 6 7 8 9,  Dali Li 10,  Ming Zhong 11
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Department of Central Laboratory, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, 201499, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 4 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 5 College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. handl@big.ac.cn.
  • 7 College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China. handl@big.ac.cn.
  • 8 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. handl@big.ac.cn.
  • 9 China National Center for Bioinformation, Beijing, 100101, China. handl@big.ac.cn.
  • 10 Shanghai Key Laboratory of Regulatory Biology, Joint Research Center for Translational Medicine, ECNU-Fengxian Hospital, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. dlli@bio.ecnu.edu.cn.
  • 11 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. drzhongming1966@163.com.
  • # Contributed equally.
PMID: 40347213 DOI: 10.1007/s11427-024-2799-6
Abstract

Dysregulation of RNA N6-methyladenosine (m6A) modification in intestinal epithelial cells (IECs) compromises intestinal homeostasis, which is critical for maintaining gastrointestinal functions, immunity, and barrier integrity in inflammatory bowel disease (IBD). Here we explored the role of m6A modification, particularly through methyltransferase like 3 (METTL3), in IBD pathology and the Apoptosis of intestinal stem cells (ISCs). Reduced m6A RNA methylation and METTL3 expression were detected in IBD tissues, which correlated with increased ISC Apoptosis and spontaneous enteritis in METTL3-deficient models; mechanistically, METTL3 depletion increased TRADD expression in a m6A-dependent manner, thereby augmenting the TNF-induced Apoptosis pathway, whereas pharmacological inhibition of TRADD ameliorated the apoptotic phenotype in METTL3-deficient models and improved survival rates in the enteritis mouse model, suggesting a novel therapeutic avenue for IBD management. Collectively, METTL3-mediated m6A RNA methylation plays a pivotal role in maintaining intestinal homeostasis and is activated in ISCs to mitigate the hyperactivity of endogenous inflammatory signals; by modulating TRADD transcript metabolism, METTL3 limits excessive ISC Apoptosis, providing insights into IBD pathogenesis and treatment strategies.

Keywords

N 6-methyladenosine; Apostatin-1; inflammatory bowel disease; intestinal Homeostasis.

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