Excess intracellular lactate represses mRNA translation and tumor progression through lactate-tRNA charging.

Tumor cells rely on sustained protein synthesis despite fluctuating metabolic stress. To examine how metabolic state directly influences translational output, we investigated lactate utilization. Intracellular accumulation of lactate, a central glycolytic product, acutely represses mRNA translation. Mechanistically, alanyl-tRNA synthetase 1 (AARS1) charges tRNAs with lactate instead of amino acids. Unlike the rapid and selective transfer of alanine to cognate tRNAAla, slower lactyl transfer permits lactate modification of non-cognate tRNAs, broadly compromising elongation fidelity. Functionally, this direct metabolic control over a fundamental process of the central dogma reshapes the translatome, operating as an intrinsic metabolic brake that aligns biosynthetic capacity with energy state. Notably, aggressive tumors elevate lactate transporters, limiting intracellular lactate accumulation and evading translational repression. Pharmacological blockade of monocarboxylate transporters restores intracellular lactate accumulation, re-establishes translational repression, and impairs tumor progression in mice. These findings uncover a metabolite-tRNA charging event directly rewiring translational output and reveal a metabolic vulnerability with therapeutic potential.