Targeting glycolysis: exploring a new frontier in glioblastoma therapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses significant threat to patient survival due its treatment resistance and rapid recurrence.Current options, including maximal safe surgical resection, radiotherapy, temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into pivotal GBM, with particular focus on multifaceted roles lactate, key product, within microenvironment (TME). Lactate been implicated promoting cell proliferation, invasion, immune evasion. Additionally, this systematically analyzes potential therapeutic strategies targeting molecules pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), Dehydrogenase A (LDHA). These studies provide novel perspective for treatment. Despite progress made existing research, challenges remain, drug penetration across blood-brain barrier, side effects, resistance. Future research will aim address these by improving delivery, minimizing exploring combination therapies immunotherapy develop more precise effective personalized GBM.

Language: Английский

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Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

ABSTRACT Oncogenes hyperactive lactate production, but the mechanisms by which facilitates tumor growth are unclear. Here, we demonstrate that is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives production from [U- 13 C]-glucose DMGs. Lactate activates nucleoside diphosphate NME1 via lactylation promotes synthesis of triphosphates proliferation. Importantly, show this mechanistic link between glycolysis provides a unique opportunity deuterium metabolic imaging Spatially mapping 2 H-lactate [6,6- H]-glucose allows visualization metabolically active lesion an early readout response to standard-of-care radiation targeted therapy precedes extended survival reflects pharmacodynamic alterations at tissue level preclinical DMG models vivo clinical field strength (3T). In essence, have identified H3K27M-lactate-NME1 axis proliferation non-invasive STATEMENT OF SIGNIFICANCE This study establishes role driving glucose using DMI clinically relevant models. Our studies lay foundation precision patients.

Language: Английский

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Lactylation in health and disease: physiological or pathological?

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1787 - 1821

Published: Jan. 2, 2025

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles different aspects of energy metabolism signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as novel posttranslational modification (PTM). Research indicates that Kla essential balancing mechanism variety organisms involved many biological processes pathways. closely related to disease development represents potential important new drug target. In line with existing reports, we searched for newly discovered sites on histone nonhistone proteins; reviewed the mechanisms (particularly focusing enzymes directly reversible regulation Kla, including "writers" (modifying enzymes), "readers" (modification-binding "erasers" (demodifying enzymes); summarized crosstalk between PTMs help researchers better understand widespread distribution diverse functions. Furthermore, considering "double-edged sword" role both pathological contexts, this review highlights "beneficial" states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) "detrimental" pathogenic or inducive effects processes, particularly malignant tumors complex nontumor diseases. We also clarify molecular health disease, discuss feasibility therapeutic Finally, describe detection technologies their applications diagnosis clinical settings, aiming provide insights treatment diseases accelerate translation from laboratory research practice.

Language: Английский

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Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 26, 2025

Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming order modulate specific pathways, providing metabolites that promote GBM cells proliferation limit efficacy treatments. Indeed, remodels glucose metabolism undergoes Warburg effect, fuelling glycolysis even when oxygen available. Moreover, recent evidence revealed rewiring nucleotide, lipid iron metabolism, not only an increased growth, but also radio- chemo-resistance. Thus, while on hand advantage for GBM, other it may represent exploitable target hamper progression. Lately, number studies focused drugs targeting uncover their effects therapy resistance, demonstrating some these are effective, combination with conventional treatments, sensitizing radiotherapy chemotherapy. However, heterogeneity could lead plethora alterations among subtypes, hence treatment might be effective proneural mesenchymal ones, which more aggressive resistant approaches. review explores key mechanisms involvement highlighting how acts as double-edged sword taking into account pathways seem offer promising options GBM.

Language: Английский

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Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: March 8, 2025

Cancer remains the leading cause of mortality worldwide, and emergence drug resistance has made identification new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct glycolysis with limited ATP-producing capacity, recently gained recognition critical signaling molecule. It plays key role not only in cancer cell metabolism but also shaping tumor microenvironment (TME). Histone lysine lactylation, newly identified post-translational modification, been shown to influence range cellular processes cancer. Current research focuses on mechanisms functions histone lactylation cancer, including its gene expression regulation, signal transduction, protein synthesis. However, despite these advancements, there are still plenty barriers quest unravel modification. The single-cell spatial transcriptomics may offer valuable insights for selecting targets. This review provides comprehensive summary applications modification clinical settings. Through detailed analysis, we identify challenges limitations that exist current landscape. These lay groundwork future studies by highlighting promising directions.

Language: Английский

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Association of B cells and the risk of glioblastoma: a bidirectional two sample mendelian randomization study

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Background Glioblastoma (GBM) represents an exceptionally aggressive form of primary malignant brain neoplasm, distinguished by its rapid growth kinetics, unfavorable prognostic indicators, and associated high mortality rates. To date, the exploration B-cell involvement in GBM remains relatively underexplored. Methods The two-sample Mendelian Randomization (MR) analysis was used to assess causal relationship between 190 B cell phenotypes GBM. Bayesian Weighted (BWMR) also employed complement MR analysis, sensitivity analyses were conducted robustness results. Result Our results demonstrate a association two risk Specifically, IgD + CD24 %B is significantly with reduced (IVW OR = 0.676, 95% CI 0.507–0.901, P_ivw 0.008); CD38 on Plasma Blast-Plasma Cell lower 0.789, 0.626–0.995, 0.045). Conclusion study suggests potential connection through bidirectional combined BWMR providing preliminary basis for future research.

Language: Английский

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Moonlighting functions of glucose metabolic enzymes and metabolites in cancer

Nature reviews. Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Language: Английский

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Single-cell and spatial transcriptomic insights into glioma cellular heterogeneity and metabolic adaptations

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Glioblastoma, one of the most aggressive and heterogeneous malignant tumors, presents significant challenges for clinical management due to its cellular metabolic complexity. This review integrates recent advancements in single-cell RNA sequencing (scRNA-seq) spatial transcriptomics elucidate glioblastoma’s heterogeneity reprogramming. Diverse subpopulations, including proliferative cells, stem-like mesenchymal-like immune-related contribute tumor progression, treatment resistance, microenvironmental interactions. Spatial has further revealed distinct distributions these highlighting differences activities between core periphery. Key adaptations, such as enhanced glycolysis, fatty acid oxidation, glutamine metabolism, play critical roles supporting growth, immune evasion, therapeutic resistance. Targeting pathways, especially combination with immunotherapy, represents a promising avenue glioblastoma treatment. emphasizes importance integrating multi-omics technologies decode landscape explore novel strategies. By addressing current challenges, redundancy spatiotemporal dynamics, this work provides insights into advancing precision medicine glioblastoma.

Language: Английский

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Lactylation in Glioblastoma: A Novel Epigenetic Modifier Bridging Epigenetic Plasticity and Metabolic Reprogramming

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3368 - 3368

Published: April 4, 2025

Glioblastoma, the most common and aggressive primary malignant brain tumor, is characterized by a high rate of recurrence, disability, lethality. Therefore, there pressing need to develop more effective prognostic biomarkers treatment approaches for glioblastoma. Lactylation, an emerging form protein post-translational modification, has been closely associated with lactate, metabolite glycolysis. Since initial identification lactylation sites in core histones 2019, accumulating evidence shown critical role that plays glioblastoma development, assessment poor clinical prognosis, immunosuppression, which provides fresh angle investigating connection between metabolic reprogramming epigenetic plasticity cells. The objective this paper present overview roles expanding field research explore practical value developing novel plans combining targeted therapy immunotherapy.

Language: Английский

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Lactylation in cancer progression and drug resistance

Drug Resistance Updates, Journal Year: 2025, Volume and Issue: unknown, P. 101248 - 101248

Published: April 1, 2025

Language: Английский

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