Lactate promotes mRNA translation in colorectal cancer cells through eEF2 lactylation

Aberrant mRNA translation contributes to tumorigenesis. Enhanced glycolysis and the resulting lactate accumulation reprogram cancer cell metabolism to support malignancy, yet how lactate modulates mRNA translation in cancer remains poorly understood. Here, we identify a novel mechanism whereby lactate promotes translation in colorectal cancer (CRC) through lysine lactylation of eukaryotic elongation factor 2 (eEF2). Lactate treatment enhances CRC cell proliferation, migration, and global protein synthesis. Mechanistically, components of the translational machinery, including eEF2, undergo lactylation upon lactate exposure. Mutation analysis revealed that K439 and K594 are lactylation sites on eEF2. Lactylation of eEF2 maintains translational efficiency and fidelity, as mutations at K439 and K594 decrease global translation and increase frameshifting errors. Correspondingly, lactylation at K439 and K594 is required for cancer cell proliferation and migration. Collectively, these findings reveal eEF2 lactylation as a key metabolic-translational axis linking lactate accumulation to efficient and accurate protein synthesis, thereby facilitating CRC progression.