Lactylation-Driven Metabolic Regulation in Cancer Biology

Lactylation, a post-translational modification in which lactate-derived moieties are appended to lysine residues on histone and non-histone proteins, has emerged as a pivotal link between tumour metabolism and gene regulation. Cancer cells frequently adopt the Warburg effect, fermenting glucose into lactate even in the presence of oxygen, thereby elevating intracellular and extracellular lactate pools. Accumulated lactate serves not merely as a metabolic by-product but as a signalling metabolite that can be converted enzymatically into lactyl-CoA and deposited onto key proteins by specialised transferases and removed by delactylases. Lactylation remodels chromatin structure, modulates transcriptional programmes governing cell cycle regulators, DNA repair factors and immune checkpoints, and alters the function of non-histone substrates involved in cell death pathways. Through these mechanisms, lactylation contributes to genomic stability or instability, shapes the tumour microenvironment by driving immunosuppression, and influences therapeutic response by promoting resistance to chemotherapy or sensitising cells to novel modalities such as cuproptosis. Growing evidence underscores a dynamic interplay between glycolytic flux, lactate signalling and epigenetic reprogramming, offering new targets for cancer therapy and precision medicine.

Research from Nature Portfolio

Recent studies have demonstrated that lactate-driven modification of DNA repair machinery can underpin chemotherapy resistance. One investigation revealed that lactylation of the NBS1 subunit at a specific lysine residue is essential for assembly of the MRN complex and efficient homologous recombination following double-strand breaks. Inhibition of lactate production or blocking the responsible lactyl-transferase attenuated NBS1 lactylation, compromised DNA repair fidelity and sensitised cancer cells to genotoxic therapy. In parallel, a separate report uncovered that a non-histone methyltransferase is lactylated under copper stress in gastric tumours, thereby potentiating m6A-dependent maturation of a key apoptotic regulator and triggering copper-induced cell death, or cuproptosis. Modulating the balance of the corresponding writer and eraser enzymes enhanced the efficacy of copper ionophores in preclinical models, pointing to lactylation as both a biomarker and a vulnerability in refractory malignancies.

Lactylation-Driven Metabolic Regulation in Cancer Biology publication trend

The graph below shows the total number of articles in lactylation-driven metabolic regulation in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Lactylation: A covalent attachment of lactate-derived groups to lysine residues on proteins, integrating metabolic state with regulation of protein function.

Warburg effect: The propensity of cancer cells to preferentially convert glucose to lactate under aerobic conditions, facilitating rapid ATP generation and biosynthetic precursor production.

Histone: A class of nuclear proteins around which DNA is wrapped to form chromatin; subject to various post-translational modifications that influence gene expression.

Homologous recombination: A high-fidelity DNA double-strand break repair pathway using a homologous sequence as a template to restore genomic integrity.

Cuproptosis: A form of regulated cell death triggered by intracellular copper accumulation, leading to aggregation of lipoylated mitochondrial proteins.

Epigenetic reprogramming: Stable alteration of gene expression patterns through chemical modifications of DNA or chromatin without changes to the underlying DNA sequence.

References

1. STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduction and Targeted Therapy (2023).
2. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature (2024).
3. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nature Communications (2023).
4. Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Molecular Cancer (2024).
5. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. Genome Biology (2021).