Lactylation in gynecological malignancies: a bridge between lactate metabolism and epigenetic therapy

Lactate, once considered a metabolic waste product, is now recognized as a key regulator of cellular homeostasis and disease progression. In gynecological malignancies—including ovarian, cervical, and endometrial cancers—lactate accumulation drives a novel post-translational modification known as lactylation. This modification serves as a critical bridge between metabolic reprogramming and epigenetic regulation, promoting tumor proliferation, metastasis, and therapy resistance. Emerging therapeutic strategies targeting lactate production, transport, and lactylation itself show significant anticancer potential, particularly when combined with immunotherapy. This review explores the role of lactate and lactylation in gynecological cancers and highlights promising directions for targeted therapy.

Lactate Metabolism and Biological Functions

Lactate is primarily produced via glycolysis under anaerobic conditions or due to the Warburg effect—a metabolic hallmark of cancer where cells preferentially utilize glycolysis even in the presence of oxygen. Beyond its role as an energy substrate, lactate regulates redox balance, fatty acid synthesis, and immune cell function. In the tumor microenvironment (TME), lactate accumulation is exacerbated by metabolic disorders and contributes to immunosuppression and chemoresistance.

The Process of Lactylation

Lactylation is a reversible epigenetic modification involving the covalent attachment of lactate to lysine residues on histones and non-histone proteins. Discovered in 2019, lysine lactylation (Kla) is regulated by three classes of enzymes:

• Writers: Such as p300/CBP, which catalyze lactylation.

• Erasers: Including HDACs and sirtuins, which remove lactyl groups.

• Readers: Such as Smarca4, which recognize lactylation sites and mediate downstream effects.

Alanyl-tRNA synthetases (AARS1/2) act as intracellular lactate sensors and lactyltransferases, facilitating lactylation of targets like p53, which correlates with poor prognosis. Lactylation occurs on both histone proteins (e.g., H3K18la, H4K12la) and non-histone proteins, influencing transcription, DNA repair, autophagy, and metabolic enzyme activity.

Role of Lactylation in Gynecological Malignancies

Lactylation drives malignancy and therapy resistance across gynecological cancers through multiple mechanisms:

• Ovarian Cancer (OC):

  • H3K18la upregulates CCL18, promoting M2 macrophage polarization and immune evasion.

  • Lactylation of PFKP enhances glycolysis via PTEN modulation.

  • RAD51 lactylation improves homologous recombination repair, conferring platinum resistance.

  • H4K12la activates RAD23A and MYC, driving niraparib resistance.

• Cervical Cancer (CC):

  • H3K18la upregulates GPD2, facilitating M2 macrophage polarization.

  • DCBLD1 lactylation stabilizes glucose-6-phosphate dehydrogenase, activating the pentose phosphate pathway.

  • HPV-16 E6 inhibits G6PD lactylation, altering metabolic flux.

• Endometrial Cancer (EC):

  • H3K18la promotes USP39 expression, stabilizing PGK1 and activating the PI3K/AKT/HIF-1α pathway.

  • PFKM lactylation enhances glycolysis and invasiveness.

Epigenetic Therapy Targeting Lactylation

Therapeutic strategies aim to disrupt lactate metabolism and lactylation to reverse malignant phenotypes:

• Metabolic Interference:

  • 2-Deoxy-D-glucose (2-DG) inhibits hexokinase, reducing lactate production.

  • Tanshinone I downregulates glycolytic enzymes (e.g., LDHA, PFKP) and lowers H3K18la levels.

  • ENO1 monoclonal antibodies block glycolysis in cervical cancer.

• Lactate Transporter Inhibitors:

  • Syrosingopine and AZD3965 inhibit monocarboxylate transporters (MCT1/4), disrupting lactate shuttling.

  • CD147 regulates MCT membrane localization and is a potential drug target.

• Immunotherapeutic Strategies:

  • Lactate-driven lactylation upregulates PD-L1. Combining LDHA or MCT inhibitors with anti-PD-1/PD-L1 antibodies enhances efficacy.

  • Resveratrol inhibits glycolysis and lactate production, reducing Treg-mediated immunosuppression.

• Other Therapeutic Targets:

  • LDHA inhibitors (e.g., oxamate) induce apoptosis and autophagy.

  • Metformin, alone or with nelfinavir, reduces lactylation via SIRT3 activation.

  • Cold atmospheric plasma (CAP) downregulates USP49, enhances HDAC3 degradation, and promotes p53-mediated ferroptosis.

Challenges and Future Directions

Despite promising preclinical results, several challenges remain:

• Lactate is involved in diverse physiological processes, raising concerns about drug specificity and toxicity.

• Many lactylation-targeting agents are still in early development, with few reaching clinical trials.

• Isoform-selective inhibitors and tissue-specific delivery systems are needed to minimize off-target effects.

Future research should focus on:

• Identifying gynecological cancer-specific lactylation sites using multi-omics and machine learning.

• Developing lactylation-based prognostic models and biomarkers.

• Exploring direct targeting of lactylation enzymes (writers, erasers, readers).

• Validating combination therapies in large-scale clinical trials.

Conclusion

Lactylation represents a mechanistic link between metabolic reprogramming and epigenetic regulation in gynecological malignancies. It influences key processes such as immune evasion, DNA repair, and chemoresistance. Targeting lactate metabolism and lactylation through metabolic interference, transporter inhibition, and immunotherapy offers a promising multi-modal approach. Future efforts to improve drug specificity and validate lactylation-directed strategies in clinical settings may significantly enhance outcomes for patients with gynecological cancers.

 

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The study was recently published in the Oncology Advances.

Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.

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