A KRAS-triggered lactylation cascade forms the basis of chemotherapy resistance in colorectal cancer

ABSTRACT:

KRAS-mutant colorectal cancer (KRASmut CRC) exhibits metabolic plasticity and chemoresistance, but the underlying mechanisms remain incompletely understood. Here, we show in CRC cells and organoids that KRAS-driven lactate accumulation promotes MCT1 K224 lactylation, which stabilizes mitochondrial MCT1 by limiting MUL1-dependent ubiquitination and degradation. This increases mitochondrial pyruvate availability and enhances pyruvate carboxylase-dependent aspartate and pyrimidine synthesis, promoting 5-fluorouracil (5-FU) resistance in CRC cells and xenografts. Mechanistically, SUGCT, previously characterized as a CoA transferase, functions as a lactyl-CoA-dependent lysine lactyltransferase that directly catalyzes MCT1 K224 lactylation. KRAS-ERK-TFCP2 signaling upregulates SUGCT, coupling lactate production to anabolic metabolism. Pharmacological TFCP2 inhibition with FQI1 suppresses SUGCT expression and MCT1 lactylation and sensitizes KRASmut CRC organoids and xenografts to 5-FU. Together, these findings define a KRAS-ERK-TFCP2-SUGCT-MCT1 lactylation axis linking glycolytic rewiring to pyrimidine-dependent chemoresistance.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS16031 | MetaboLights | 2026-10-16

REPOSITORIES: MetaboLights