TY  - EJOU
AU  - Rastogi, Vishal 
AU  - Verma, Deepak 
AU  - Verma, Saurabh 
AU  - Haloi, Prakash 
AU  - Kapoor, Shruti 
AU  - Chitme, Havagiray R. 
AU  - Muniraj, Nethaji 
AU  - Saroj, Priyanka 

TI  - Epigenomic and Metabolic Interplay in the Development of Metastatic Brain Tumors
T2  - Oncology Research

PY  - 2026
VL  - 34
IS  - 3
SN  - 1555-3906

AB  - 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.
KW  - Metabolic reprogramming; brain tumor; epigenetic alteration

DO  - 10.32604/or.2026.072620