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. fuming_li@fudan.edu.cn.
# 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.

Products

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Description

Target

Research Area
HY-100017

BAY-876

99.67%, GLUT1 Inhibitor

GLUT

Cancer

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