(Press-News.org) 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.
Full text
http://xiahepublishing.com/2996-3427/OnA-2025-00020
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.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.
END
Background and objectives
Emerging evidence implicates immune dysregulation and neuroinflammation in the pathogenesis of epilepsy, yet the causal mechanisms remain unclear. This study aimed to investigate the causal effects of immune cells and inflammatory proteins on epilepsy and evaluate the mediating role of inflammatory proteins.
Methods
This study utilized the largest available genome-wide association study data on immune cell phenotypes and inflammatory proteins as exposures, and epilepsy genome-wide association study data from the FinnGen dataset as outcomes. Five Mendelian randomization (MR) methods were applied within a two-sample MR framework to assess causal effects. Furthermore, ...
About The Study: The results of this cohort study suggest that, for older adults, poor olfaction as assessed by a single smell identification test is associated with a higher coronary heart disease risk.
Corresponding Author: To contact the corresponding author, Honglei Chen, PhD, email chenho19@msu.edu.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamaoto.2025.3740)
Editor’s Note: Please see the article for additional information, including other authors, author contributions ...
About The Study: The findings of this study suggest that maintaining a moderate level of physical activity of approximately 17 metabolic equivalent task-hours/week (i.e., 5 hours of brisk walking or 2 hours of running each week) over 3 decades was sufficient to achieve optimal benefit in reducing digestive system cancer risk.
Corresponding Author: To contact the corresponding author, Edward L. Giovannucci, MD, ScD, email egiovann@hsph.harvard.edu.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamaoncol.2025.4185)
Editor’s Note: Please see the article for additional information, ...
About The Study: The findings of this study highlight the persistence of misbeliefs and knowledge gaps about the link between alcohol and cancer among U.S. adults, which may contribute to the continuous increase in alcohol consumption. Individuals who drink alcohol were more likely to believe that alcohol consumption has no effect on cancer risk, which is alarming, given the growing burden of alcohol-related cancers in the U.S.
Corresponding Author: To contact the corresponding author, Sanjay Shete, PhD, email sshete@mdanderson.org.
To access the embargoed study: Visit our For The Media ...
Researchers at The University of Texas MD Anderson Cancer Center, in collaboration with BostonGene, conducted the largest and most comprehensive molecular analysis of renal medullary carcinoma (RMC), a rare and aggressive form of kidney cancer, leading to the identification of TROP2 as a promising therapeutic target.
What is the key discovery in this research and why is it significant?
By evaluating 25 patient samples, the researchers identified overexpression of TROP2 and several other cell-surface proteins in RMC, as well as upregulation of the Hippo pathway. These findings led to the exploration of sacituzumab govitecan, a TROP2-targeted antibody-drug ...
Some common hormonal contraceptives are linked to a slightly higher risk of breast cancer than others. This is shown by a new Swedish study from Uppsala University, in which researchers followed more than two million women and teenage girls in Sweden to identify how different hormonal contraceptives affect the risk of breast cancer.
Peer-review / Observational study / Women
In Sweden, hundreds of thousands of women use hormonal contraceptives every year. Over time, new products have been developed – from combined contraceptive pills ...
Stroke is a leading cause of death and disability, affecting 1 in 4 people during their lifetime. Stroke happens when blood vessels in the brain get clogged or damaged, impairing blood flow and oxygen supply to the brain, which leads to death of neurons and other brain cells. Although brain damage can be limited by interventions to restore blood flow, most stroke survivors experience some lifelong impairments of e.g. speech, movement, or cognitive function.
Despite the existence of immature stem cells in the brain, their role in repair is uncertain and the brain’s ...
If cancer is a disease of overabundance, where cells divide without restraint and tumors grow despite the body’s best interests, then degenerative diseases are disorders of deprivation.
When malfunctions occur in the biological machinery our muscles or our brains use for renewal and repairs, these tissues gradually wither. This kind of decline is the hallmark of diseases such as Alzheimer’s disease or Duchenne muscular dystrophy.
Scientists have long sought to develop treatments that enhance the muscle’s self-renewal capabilities ...
More than half of American adults misunderstand or underestimate the link between alcohol consumption and cancer
Alcohol drinkers are especially likely to believe that drinking has no effect on cancer risk
Correcting these misbeliefs may strengthen adherence to U.S. Surgeon General’s alcohol consumption guidelines to lower cancer risk
HOUSTON, OCTOBER 30, 2025 – Despite clear evidence linking alcohol use to increased cancer risks, public awareness of this connection remains low in the U.S., according to new research from The University of Texas MD Anderson ...
(Toronto, October 30, 2025) JMIR Publications invites submissions to a new section titled "Digital Health Strategic Planning" in its open access journal Journal of Medical Internet Research. The premier, peer-reviewed journal is indexed in in all major literature indices including National Library of Medicine(NLM)/MEDLINE, PubMed, PMC, Scopus, DOAJ, Clarivate (which includes Web of Science (WoS)/ESCI/SCIE), and others.
The integration of digital health into global policy, accelerated by the COVID-19 pandemic and rapid technological progress, has highlighted a critical need for systematic digital ...
