α-ketoglutarate maintains AMPK translation for energy sensing in human cancer cells_lipid

The energy sensor 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) controls 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 cell death . Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK translation. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose starvation. Finally, co-targeting oncogenic YBX1 and GLUT1 creates a synthetic lethality and therapeutically 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.