The epigenetic–metabolic axis in gliomas: Mechanisms and implications

Gliomas are difficult to treat. Epigenetic changes – without altering DNA sequence – drive tumor growth and therapy resistance. Metabolic intermediates (acetyl‑CoA, SAM, α‑KG, NAD⁺) act as cofactors for epigenetic enzymes, linking nutrient availability to gene expression. Diabetes worsens glioma progression via hyperglycemia, inflammation, and epigenetic reprogramming. Tumors near brain autonomic centers may disrupt heart function, increasing sudden death risk, especially in diabetics. This review integrates metabolism, epigenetics, and brain‑heart signaling to propose personalized treatments targeting both tumor and systemic health.

Introduction
Gliomas range from low‑grade astrocytomas to glioblastoma (GBM). Epigenetics (DNA methylation, histone modifications, chromatin remodeling, non‑coding RNAs) regulates gene expression without changing DNA sequence and is key to tumor progression and therapy resistance.

Epigenetic Mechanisms

• DNA methylation: DNMTs (DNMT1, DNMT3A, DNMT3B) silence tumor suppressors (PTEN, RB1, CDKN2A/B). Hypermethylation promotes immune evasion (PD‑L1 upregulation).

• Histone modifications: Acetylation (HDACs), methylation (H3K27, H3K9), lactylation, crotonylation, etc. Dysregulation activates oncogenes and supports stemness.

• Chromatin remodeling: SWI/SNF, ISWI, CHD4, INO80 complexes control DNA repair and cell cycle. Their dysfunction promotes GBM growth and radiation resistance.

• Non‑coding RNAs: miR‑21 (oncogenic), miR‑34a (tumor suppressor), HOTAIR (stemness), circFBXW7 (sponge) regulate glioma progression. Circulating ncRNAs are promising biomarkers.

Metabolic‑Epigenetic Feedback Loops
Metabolites are epigenetic cofactors (Table 2):

• α‑KG → promotes differentiation.

• 2‑HG (mutant IDH) → blocks differentiation, increases stemness.

• Acetyl‑CoA → activates MYC.

• SAM → silences tumor suppressors.

• NAD⁺ → regulates stemness via sirtuins.

• Lactate → lactylation promotes growth and immune evasion.

• SCFAs → inhibit HDACs.

• BHB → supports metabolic adaptation.
  These loops reinforce oncogenic programs.

Diabetes as a Catalyst
Hyperglycemia fuels glycolysis, activates PI3K/AKT/mTOR, causes inflammation (IL‑6, TNF‑α), and generates AGEs that non‑enzymatically modify histones and activate RAGE/NF‑κB. Hyperglycemia also damages the BBB, increases VEGF, and impairs autonomic function, causing hypoxia and HIF‑1α stabilization.

Brain‑Heart Axis
Gliomas near autonomic centers (insula, hypothalamus, brainstem) can disrupt heart function via ANS and HPA axis dysregulation, leading to arrhythmias and sudden death. Diabetes worsens this via autonomic neuropathy and chronic inflammation. Pro‑inflammatory cytokines further impair endothelial function and cardiac health.

Future Directions

• Nanoparticle delivery of epigenetic drugs across the BBB.

• Metabolic management (GLP‑1 agonists, glucose control).

• Advanced imaging (DTI, PET‑MRI) and liquid biopsy (ctDNA, miRNAs, circRNAs).

• Digital neuro‑surveillance (wearable EEG, machine learning).

Conclusions
Metabolic‑epigenetic feedback loops are central to glioma progression and intersect with diabetes and cardiovascular dysfunction. The brain‑heart axis shows that gliomas affect systemic health. Future personalized treatments must target multiple vulnerabilities (metabolic, immune, vascular, epigenetic) to improve outcomes.

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https://www.xiahepublishing.com/2472-0712/ERHM-2025-00042

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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