α-Ketoglutarate drives carnitine synthesis to promote histone acetylation and homologous recombination DNA repair in cancer cells (nature.com)

• αKG promotes resistance to DNA-damaging agents via TMLHE-dependent carnitine synthesis.
• Carnitine-derived acetyl-CoA drives site-specific histone acetylation (H3K23ac, H4K8ac, H4K12ac).
• Histone acetylation is required for homologous recombination (HR) repair of DNA double-strand breaks.
• High TMLHE or acetylcarnitine correlates with poor progression-free survival in patients.

"A new study in Nature identifies a metabolic axis linking α-ketoglutarate (αKG) to carnitine synthesis via the enzyme TMLHE, which promotes site-specific histone acetylation (H3K23ac, H4K8ac, H4K12ac) and homologous recombination (HR) DNA repair in HR-proficient cancer cells. Depletion of αKG or TMLHE sensitizes cells to DNA-damaging agents (olaparib, cisplatin), while supplementation with αKG or L-carnitine rescues resistance. High TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This pathway offers a potential metabolic vulnerability for overcoming chemoresistance."