Open Access
REVIEW
Epigenomic and Metabolic Interplay in the Development of Metastatic Brain Tumors
Vishal Rastogi1,#, Deepak Verma2,#, Saurabh Verma3, Prakash Haloi1, Shruti Kapoor4, Havagiray R. Chitme1, Nethaji Muniraj5,*, Priyanka Saroj1,*
1 Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Noida, 201313, India
2 Department of Oncology, Johns Hopkins University, Baltimore, MD 21210, USA
3 Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, 201313, India
4 Molecular, Cellular and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA
5 Center for Cancer and Immunology Research, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC 20010, USA
* Corresponding Author: Nethaji Muniraj. Email: 
; Priyanka Saroj. Email: 
# Equal first author contribution
(This article belongs to the Special Issue: Novel Strategies in the Diagnosis, Prediction, Monitoring, and Treatment of Brain Tumors)
Oncology Research https://doi.org/10.32604/or.2026.072620
Received 31 August 2025; Accepted 05 January 2026; Published online 21 January 2026
Abstract
Metastatic brain tumors undergo profound metabolic–epigenetic reprogramming driven by the unique constraints of the brain microenvironment. Hypoxia-inducible factor-1α (HIF1α) enhances glycolytic flux, lactate accumulation, and histone lactylation, collectively supporting metastatic colonization and immune evasion. Key metabolites including acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate (α-KG), fumarate, and 2-hydroxyglutarate (2-HG)—directly modify chromatin states by regulating histone acetyltransferases, DNA/histone methyltransferases, and α-KG dependent dioxygenases such as Ten-Eleven Translocation (TET) enzymes and lysine demethylases (KDMs). These metabolic shifts result in aberrant DNA methylation, histone lysine residue at position 27 on Histone H3 (H3K27) trimethylation, and depletion of 5-hydroxymethylcytosine (5hmC), all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System (CNS) tumors. Additionally, the blood–brain barrier (BBB) and blood–tumor barrier (BTB) impose nutrient restrictions and induce metabolic dependency on glutamine, acetate, and lactate shuttling, thereby reshaping epigenetic enzyme activity. We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity, stemness, and therapeutic resistance. Understanding these coupled pathways reveals vulnerable nodes such as HIF1α signaling, α-KG–dependent demethylation, and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors. The present review aims to provide in-depth insights into epigenetic regulation, including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming, highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.
Keywords
Metabolic reprogramming; brain tumor; epigenetic alteration
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