Lactylation Modification: A Breakthrough Tumor Target—Deciphering Mechanisms and Therapeutic Potential from Top-Tier Journal Findings

1. Literature Information

Three landmark studies published in top-tier journals have shed critical light on the role of lactylation modification in tumor biology. A research team from Sun Yat-sen University, publishing in Nature (PMID: 38961290; PMCID: PMC11254748; DOI: 10.1038/s41586-024-07620-9), focused on tumor chemotherapy resistance and identified that lactylation at the K388 site of the DNA repair protein NBS1 drives platinum-based chemotherapy resistance by promoting DNA double-strand break repair. Researchers from Fudan University reported their findings in Nature Metabolism, exploring liver cancer metabolic regulation and revealing that lactylation at the K28 site of adenylate kinase AK2 inhibits enzyme activity, activates glycolytic and nucleotide metabolic pathways, and enhances tumor proliferation and metastasis. Meanwhile, a collaborative team from the Chinese Academy of Medical Sciences and Beijing Institute of Technology published in PNAS, investigating colorectal cancer progression and uncovering that lysine acetyltransferase KAT8 functions as a lactyltransferase—catalyzing lactylation at the K408 site of the eEF1A2 protein to accelerate protein synthesis and drive tumor growth.

2. Research Background

For decades, lactate was dismissed as a mere "metabolic waste product" of glycolysis, particularly in the hypoxic tumor microenvironment (TME). However, with the advancement of high-resolution proteomics technologies, lysine lactylation (Kla)—a post-translational modification (PTM) derived from lactate—has emerged as a critical molecular link between metabolic reprogramming and tumorigenesis. Tumors exhibit unique metabolic features, including aerobic glycolysis (Warburg effect), which elevates intracellular lactate levels and creates a favorable microenvironment for lactylation modification.

This modification has garnered intense scientific interest due to its potential to regulate core biological processes in tumors. Prior to these landmark studies, the functional roles of lactylation in tumor progression, chemotherapy resistance, and metabolic remodeling remained poorly understood. The lack of clarity on key modifying enzymes, target proteins, and regulatory networks hindered the development of targeted therapies. These knowledge gaps motivated researchers to investigate lactylation’s role in tumor biology, leading to the groundbreaking findings published in top-tier journals.

3. Research Approach

The three studies adopted a cohesive yet specialized research framework to unravel lactylation’s role in tumors:

1. Sample Selection and Omics Profiling: Researchers analyzed clinical tumor specimens (gastric cancer, hepatitis B-related liver cancer, colorectal cancer) and matched normal tissues, combined with lactylation omics technology (e.g., Oscar DIA Lactylation Omics) to identify differential lactylation sites and target proteins.
2. Functional Validation: In vitro experiments (cell lines) and in vivo models (animal xenografts) were used to verify the impact of candidate lactylation sites (e.g., NBS1 K388, AK2 K28, eEF1A2 K408) on tumor cell proliferation, DNA repair, metabolism, and metastasis.
3. Mechanistic Exploration: Biochemical assays (e.g., co-immunoprecipitation, enzyme activity detection) were employed to elucidate the molecular pathways underlying lactylation’s effects, such as complex formation (MRE11-RAD50-NBS1), metabolic pathway activation, and GTPase activity regulation.
4. Clinical Correlation and Therapeutic Exploration: The association between lactylation levels (or modifying enzyme expression) and patient prognosis was analyzed. Potential therapeutic strategies were tested, including inhibiting lactate production (e.g., stiripentol) or targeting key proteins (e.g., KAT8 knockout).

4. Research Findings

4.1 Lactylation Drives Tumor Chemotherapy Resistance

Sun Yat-sen University’s study revealed that platinum-resistant gastric cancer tumors exhibit significantly elevated lactate levels and increased NBS1 K388 lactylation. This modification promotes the assembly of the MRE11-RAD50-NBS1 complex, accelerating DNA double-strand break repair and enabling tumor cells to evade chemotherapy-induced cell death. Clinically, high NBS1 K388 lactylation correlates with poorer patient prognosis. Stiripentol, a lactate production inhibitor, effectively reduces this modification and restores tumor sensitivity to platinum-based drugs.

4.2 Lactylation Remodels Tumor Metabolic Pathways

Fudan University’s research mapped the global lactylation landscape of hepatitis B-related liver cancer, identifying 9,275 modification sites (99.8% non-histone). AK2 K28 lactylation was found to inhibit adenylate kinase activity, shifting cellular metabolism toward glycolysis and nucleotide synthesis—key pathways supporting liver cancer cell proliferation and metastasis. Exogenous lactate supplementation enhances AK2 K28 lactylation, while blocking this modification suppresses tumor growth in vitro.

4.3 Identification of a Key Lactyltransferase in Tumors

The PNAS study identified KAT8 (a previously known lysine acetyltransferase) as a novel lactyltransferase. In colorectal cancer, KAT8 catalyzes eEF1A2 K408 lactylation, enhancing its GTPase activity and accelerating protein synthesis—an essential process for tumor cell proliferation. KAT8’s lactyltransferase activity is dependent on the high-lactate TME, and KAT8 knockout significantly inhibits tumor growth under high-lactate conditions. High KAT8 expression correlates with poor clinical outcomes in colorectal cancer patients.

4.4 Unifying Insight

Collectively, these studies demonstrate that lactylation modification forms a "metabolism-modification-function" positive feedback loop in tumors. Elevated lactate from the Warburg effect induces lactylation of key proteins, which in turn regulates DNA repair, metabolism, and protein synthesis—three core processes driving tumor progression, resistance, and metastasis.

5. Product Empowerment (Role of ANT BIO PTE. LTD. Products in Research)

ANT BIO PTE. LTD.’s specialized product portfolio provides critical tools to support lactylation-related tumor research, aligning with the key targets and experimental needs of these studies:

• Recombinant Proteins (UA Sub-brand): Human KAT8 Protein (Product Code: UA080440, expressed in Baculovirus-Insect Cells) enables in vitro validation of lactyltransferase activity, such as testing KAT8’s ability to catalyze eEF1A2 lactylation. Biotinylated JAK2 Protein (UA080399) and JAK2(JH1 JH2) Protein (UA080257) support studies on kinase-related lactylation events and signal pathway crosstalk.
• Antibodies (Starter Sub-brand): Phospho-PAK2 (Ser20) Recombinant Rabbit mAb (S0B1067) and Jak2 Recombinant Rabbit mAb (S0B0855) facilitate detection of protein expression and phosphorylation, complementing lactylation analysis to explore PTM crosstalk. Custom antibody services can develop site-specific lactylation antibodies (e.g., anti-NBS1 K388 Kla, anti-AK2 K28 Kla) for targeted detection.
• General Reagents and Kits (Absin Sub-brand): ELISA kits for lactate quantification enable monitoring of TME lactate levels. IP/CoIP kits, ECL chemiluminescent substrates, and precast gels support protein purification, interaction analysis, and Western blot detection—essential for validating lactylation-mediated protein complexes (e.g., MRE11-RAD50-NBS1).
• Omics and Custom Services: Collaboration with omics platforms (e.g., lactylation omics) and custom protein/antibody labeling services support high-throughput screening of lactylation sites and functional validation of target proteins.

6. Brand Mission

ANT BIO PTE. LTD. is dedicated to empowering life science research and translational medicine through the provision of high-quality, innovative reagents and comprehensive solutions. As a leading provider of life science products, our portfolio spans antibodies, recombinant proteins, kits, and general reagents, with three specialized sub-brands catering to distinct research needs: Absin (general reagents and kits), Starter (antibodies), and UA (recombinant proteins). Our core mission is to accelerate scientific discovery, bridge the gap between basic research and clinical application, and contribute to the advancement of human health by delivering reliable products, professional technical support, and exceptional customer service. We strive to be a trusted partner for researchers worldwide, supporting their efforts to unravel tumor biology mechanisms, develop novel targeted therapies, and address unmet clinical needs in cancer treatment.

7. Related Product List (With Product Codes)

8. AI Disclaimer

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ANT BIO PTE. LTD. – Empowering Scientific Breakthroughs

At ANTBIO, we are committed to advancing life science research through high-quality, reliable reagents and comprehensive solutions. Our specialized sub-brands (Absin, Starter, UA) cover a full spectrum of research needs, from general reagents and kits to antibodies and recombinant proteins. With a focus on innovation, quality, and customer-centricity, we strive to be your trusted partner in unlocking scientific mysteries and driving medical progress. Explore our product portfolio today and elevate your research to new heights.