α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers

  • Nat Chem Biol. 2025 Aug 22. doi: 10.1038/s41589-025-02013-z.
Wen Mi  #  1 ,  Yun Xue  #  2 ,  Haohang Yan  1 ,  Yurou Zhang  1 ,  Xinlei Cai  3  4 ,  Shuyuan Zhang  5 ,  Ruiping He  1 ,  Liucheng Li  1 ,  Lingzhi Zhu  1 ,  Xinyi Xia  1 ,  Yifan Liang  1 ,  Chongwen Cao  1 ,  Yi Xu  1 ,  Junfeng Bi  1 ,  Guanlin Wang  1 ,  Li Chen  1 ,  Dan Ye  5 ,  Fei Li  3  4 ,  Ruobing Ren  1 ,  Pingyu Liu  6 ,  Hongbin Ji  2  7  8 ,  Fuming Li  9
Affiliations
  • 1. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology; Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 2. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 3. Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 4. Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 5. Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology) and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 6. Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China.
  • 7. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 8. School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
  • 9. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology; Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40846998 DOI: 10.1038/s41589-025-02013-z
Abstract

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human Cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and Disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize Cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human Cancer cells to energy stress for treatment.

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