2. Academic Validation
  3. Energy status orchestrates YTHDF1 phase separation and tumorigenesis

Energy status orchestrates YTHDF1 phase separation and tumorigenesis

  • Cell Rep. 2025 Nov 25;44(11):116466. doi: 10.1016/j.celrep.2025.116466.
Haisheng Yu 1,  Jie Shi 1,  Rongrong He 2,  Xue Zhang 1,  Shuchao Ren 2,  Qiushi Chen 3,  Haiou Li 4,  Wenjun Xiong 1,  Yingmeng Yao 1,  Wenjing Song 5,  Yishuang Sun 1,  Chuan He 1,  Xixin Xing 1,  Gaoshan Xu 1,  Xiyong Wang 1,  Yan Ren 6,  Zhipeng Zhou 2,  Zongbi Yi 7,  Jinfang Zhang 8
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
  • 3 Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong Science Park, Hong Kong 999077, China; Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong 999077, China.
  • 4 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 6 Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 7 Department of Radiation and Medical Oncology, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 8 Department of Radiation and Medical Oncology, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
PMID: 41171760 DOI: 10.1016/j.celrep.2025.116466
Abstract

Aberrant energy status impacts the initiation and progression of tumorigenesis, although the underlying mechanisms remain poorly understood. Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a key sensor of cellular energy stress, is activated to facilitate metabolic adaptation and regulate tumorigenesis. Here, we reveal that energy deprivation-induced activation of AMPK phosphorylates YTHDF1 at Ser198, counteracting its O-GlcNAcylation. This phosphorylation alters the functional properties of YTHDF1 by suppressing its phase separation and interaction with the translation initiation factor eIF3b, ultimately reducing protein translation. Notably, enhancing YTHDF1 phosphorylation to antagonize its O-GlcNAcylation through AMPK agonists or ketogenic diet effectively inhibits tumor cell growth both in vitro and in vivo. These findings elucidate a regulatory mechanism that links cellular energy status to YTHDF1 post-translational modifications and highlight the therapeutic potential of targeting YTHDF1-mediated pathways via metabolic interventions for Cancer treatment.

Keywords

AMPK; CP: Metabolism; O-GlcNAcylation; OGT; YTHDF1; breast cancer; energy status; ketogenic diet; phase separation; phosphorylation; protein synthesis.

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