安普克
计算生物学
化学
细胞生物学
计算机科学
纳米技术
生物化学
生物
蛋白激酶A
磷酸化
材料科学
作者
Mi Wen,Xue Yun,Haohang Yan,Yurou Zhang,Xinlei Cai,Shuyuan Zhang,Ruiping He,Liucheng Li,Lingzhi Zhu,Xinyi Xia,Yifan Liang,C Cao,Yi Xu,Junfeng Bi,Guanlin Wang,Li Chen,Dan Ye,Fei Li,Ruobing Ren,Pingyu Liu
标识
DOI:10.1038/s41589-025-02013-z
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.
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