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

Abstract

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

Keywords: epigenetic remodeling; glioblastoma; lactylation; metabolic reprogramming.

Figure 1

Metabolic and epigenetic interactions through lactylation. Glycolytic metabolic reprogramming and epigenetic plasticity associated with lactylation enable information interchange via lactate and trigger corresponding signal transduction to promote the malignant characteristics of the tumor.

Figure 2

Role of lactate and lactylation in GBM. This schematic delineates the lactate–lactylation regulatory network. The glycolytic phenotype, driven by HIF-1α and c-Myc and restrained by p53, regulates lactate production, which is exported via MCT4 to acidify TME, fostering malignant progression. Intracellular lactate, derived from both endogenous glycolysis and MCT1-mediated uptake, induces histone and non-histone lactylation, regulating gene expression and signaling pathways, further driving tumor invasion, metastasis, and immunosuppression. The current targeting strategies mainly target lactate production (e.g., DCA, Stiripentol) and transport (MCT inhibitors), which are highlighted in red in the figure, providing potential interventions to disrupt this epigenetic–metabolic network in GBM. Abbreviations: HIF-1, hypoxia-inducible factor 1; GLUT, glucose transporter ; TME, tumor microenvironment; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; GPR, G-protein-coupled receptor; CAF, cancer-associated fibroblast; Treg, regulatory T cells; DCA, dichloroacetate; Dex, dexmedetomidine; lactyl-CoA, lactyl-coenzyme A; MDMs, monocyte-derived macrophages; CHC, α-cyano-4-hydroxycinnamate.