Lysine Lactylation: When Metabolism Meets Gene Expression

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The Warburg effect, a hallmark of cancer metabolism, describes how cancer cells preferentially convert glucose to lactate even in oxygen-rich conditions. While once considered a mere byproduct of glycolysis, lactate is now recognized as a key regulatory molecular in cellular function. One of its most significant roles is in lysine lactylation (Kla), a post-translational modification that influences gene regulation, immune modulation, and disease progression.

Biological Functions of Lactylation

Lactyl-CoA serves as an L-lactate donor, modifying lysine residues on proteins. Additionally, AARS1/2 enzymes can directly catalyze lactylation using lactate itself.

Lactylation plays a significant role in gene regulation, protein function, and various biological processes. By modifying histones (e.g. Lys18 on histone H3), lactylation enhances transcription elongation and upregulates m6A-related enzymes METTL3 and YTHDF2. lactylation also directly influence transcription factors, thereby affecting the expression levels of key disease-related proteins and non-coding genes.

Lactylation alters protein structure, impacting protein stability and function. For example, lactylation stabilizes β-catenin and facilitates its cellular entry via MCT1 in prostate cancer cells. Elevated HIF-1α lactylation stabilizes HIF-1α even under normoxic conditions.

In the tumor microenvironment, lactylation influences the polarization of M1 macrophages by regulating key gene expression. It may also affect other immune cells, such as tumor-infiltrating myeloid cells, further contributing to tumor growth and immune evasion.

Moreover, lactylation interacts with other post-translational modifications (PTMs), such as phosphorylation and acetylation, collectively modulating protein structure, function, and activity.

Lactylation in Disease Progression

Emerging evidence links lactylation to various diseases, providing new insights into pathogenesis and potential therapeutic strategies.

Tumorigenesis and Cancer Progression

Lactylation plays a critical role in tumorigenesis and cancer progression. Initially identified in liver cancer cells, it has since been implicated in metabolic pathways involving the TCA cycle, carbohydrate metabolism, amino acid processing, fatty acid synthesis, and nucleotide biosynthesis. Studies reveal its involvement in multiple cancers, including gastric cancer, prostate cancer, and uveal melanoma, often correlating with poor prognosis. Notable research includes:

Chen, H. et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature (2024).

Zhi Zong et al. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell (2024)

Yang, Z. et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab (2023).

Neurodegenerative Diseases

Lactylation is widely present in the brain and plays a key role in chromatin state regulation and gene expression. Research suggests neural stimulation and social stress influence lactylation levels, with implications for social behavior and anxiety-related disorders. Key findings include:

Zhou J et al. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab. (2024)

Wang, X. et al. A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology. Sig Transduct Target Ther (2024).

Cardiovascular Diseases

Lactylation plays a multifaceted role in cardiovascular health, particularly in post-myocardial infarction recovery.

Studies indicate it:

• Activates the TGF-β pathway, contributing to cardiac fibrosis and dysfunction.
• Facilitates early monocyte activation, promoting heart repair.
• Regulates neuronal death in ischemic stroke through mitochondrial apoptosis pathways.

PTM BIO’s Lysine Lactylation Antibodies

PTM BIO offers a suite of high-quality lysine lactylation antibodies to accelerate research into the role of lactylation in disease mechanisms. These tools enable researchers to explore the emerging field of lactylation with precision, offering new possibilities for therapeutic interventions across cancer, neurodegenerative diseases, and cardiovascular conditions. As lactylation research evolves, PTM BIO remains committed to empowering scientists with innovative solutions to uncover its full biological significance.