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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • Wen Mi,
  • Yun Xue,
  • Haohang Yan,
  • Yurou Zhang,
  • Xinlei Cai,
  • Shuyuan Zhang,
  • Ruiping He,
  • Liucheng Li,
  • Lingzhi Zhu,
  • Xinyi Xia,
  • Yifan Liang,
  • Chongwen Cao,
  • Yi Xu,
  • Junfeng Bi,
  • Guanlin Wang,
  • Li Chen,
  • Dan Ye,
  • Fei Li,
  • Ruobing Ren,
  • Pingyu Liu,
  • Hongbin Ji,
  • Fuming Li

摘要

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.