Epigenetic Regulation of Cancer Metabolism: Emerging Biochemical Mechanisms and Therapeutic Opportunities

Abstract: Cancer is increasingly understood as a disease of both genetic and epigenetic dysregulation, with metabolic reprogramming serving as a central driving force that reshapes the epigenome. The bidirectional crosstalk between metabolic intermediates and chromatin-modifying enzymes represents a fundamental mechanism underlying tumour initiation, progression, and therapeutic resistance. This review systematically examines the biochemical mechanisms linking cellular metabolism to epigenetic regulation in cancer, with an emphasis on clinically actionable pathways and emerging therapeutic strategies. A comprehensive narrative review of primary literature and clinical trial data published between 2020 and 2025 was conducted. Studies focusing on DNA methylation, histone modifications, RNA epitranscriptomics, oncometabolite biology, and epigenetic drug development in the context of cancer metabolism were included. Key metabolites including acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate (α-KG), succinate, fumarate, and 2-hydroxyglutarate (2-HG) are shown to directly regulate epigenetic enzyme activity, chromatin architecture, and gene expression programmes. Oncometabolites produced by mutant isocitrate dehydrogenase (IDH1/2), succinate dehydrogenase (SDH), and fumarate hydratase (FH) competitively inhibit α-KG-dependent dioxygenases, inducing hypermethylator phenotypes. Furthermore, N6-methyladenosine (m6A) RNA modification emerges as an integrator of metabolic and epitranscriptomic signals. The therapeutic landscape includes FDA-approved agents targeting DNMTs, HDACs, EZH2, and mutant IDH, alongside a rich pipeline of ACLY, ACSS2, BET bromodomain, and METTL3 inhibitors. Rational combination strategies exploiting epigenetic-metabolic vulnerabilities represent the frontier of precision oncology. Keywords: epigenetics; cancer metabolism; DNA methylation; histone modification; oncometabolite; IDH mutation; m6A; HDAC inhibitor; EZH2; therapeutic targeting.