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INTERNATIONAL CONGRESS OF

CancerGenetics

• Metabolic–Epigenetic Crosstalk in Human Disease: How Metabolites Control Gene Expression and Cellular Function

• Seyed Mohammad Kasra Esfahani,¹ Zahra Aghelan,^2,* Kimia Sadat Esfahani,³
  1. Department of Medical Laboratory Sciences, TeMS.C., Islamic Azad University, Tehran, Iran
  2. Department of Clinical Biochemistry, TeMS.C., Islamic Azad University, Tehran, Iran
  3. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
  
  
  
• Introduction: Metabolism and epigenetic regulation are increasingly recognized as interconnected processes that coordinate gene expression and cellular function. Beyond their classical roles in energy production and biosynthesis, metabolic pathways influence the epigenome by controlling the availability of metabolites that serve as substrates, cofactors, or inhibitors of chromatin-modifying enzymes. Key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, and NAD+, directly regulate DNA methylation, histone acetylation, deacetylation, and other chromatin modifications, thereby linking cellular metabolic states to gene expression. This metabolic–epigenetic interplay is bidirectional, as epigenetic mechanisms can also regulate the expression of metabolic enzymes and reshape cellular metabolic pathways. Alterations in metabolic flux can consequently modify chromatin structure and transcriptional programs, contributing to changes in cellular proliferation, differentiation, adaptation, and homeostasis. In particular, histone acylations, including acetylation, propionylation, butyrylation, succinylation, crotonylation, and β-hydroxybutyrylation, are influenced by the availability of their corresponding acyl-CoA metabolites, providing a direct molecular link between metabolism and chromatin regulation. Disruption of this crosstalk has been implicated in human diseases, including cancer, metabolic disorders, cardiovascular disease, and neurodegenerative conditions. Metabolic reprogramming may alter metabolite availability and generate oncometabolites such as 2-hydroxyglutarate, succinate, and fumarate, which can interfere with epigenetic enzymes and promote aberrant gene regulation. Therefore, this review aims to clarify how metabolic alterations modify the availability of key metabolites and, consequently, influence epigenetic mechanisms such as DNA methylation and histone modifications. Specifically, it examines how these metabolic–epigenetic interactions alter gene expression and cellular processes, including inflammation, proliferation, differentiation, and adaptation, and how their dysregulation may contribute to the development and progression of human diseases.
• Methods: This systematic review was conducted in accordance with the PRISMA 2020 guidelines. Relevant studies published between 2024 and 2026 were identified through comprehensive searches of PubMed, Scopus, and Web of Science databases using predefined keywords related to Metabolic–Epigenetic Crosstalk in Human Disease. Eligible studies were screened based on predefined inclusion and exclusion criteria, and data were synthesized qualitatively.
• Results: The collected findings provide evidence for a bidirectional relationship between cellular metabolism and epigenetic regulation, in which changes in metabolite availability can reshape chromatin organization and transcriptional activity. Short-chain fatty acids (SCFAs), particularly propionate and butyrate, emerged as important metabolic regulators of histone modifications. Their incorporation into histone lysine residues generates non-canonical acylation marks, including H3K18 propionylation, H3K18 butyrylation, H4K12 propionylation, and H4K12 butyrylation, which were associated with enhanced chromatin accessibility and changes in gene expression. More broadly, metabolite availability can influence several histone modifications, including acetylation, butyrylation, crotonylation, succinylation, and other acylation events. Metabolites such as acetyl-CoA, succinyl-CoA, lactate, S-adenosylmethionine (SAM), and 2-ketoglutarate (2-KG) can serve as substrates, cofactors, or regulatory molecules for epigenetic enzymes, thereby connecting metabolic activity with chromatin regulation. In colorectal cancer, SCFA-associated histone acylation was linked to altered Wnt/β-catenin and TGF-β signaling and changes in growth-related gene expression. Collectively, these findings highlight metabolic state as an important determinant of epigenetic regulation and cellular function.
• Conclusion: Metabolic–epigenetic crosstalk provides a mechanistic link between metabolic imbalance and persistent changes in cellular behavior. Metabolic reprogramming can alter the intracellular levels of metabolites that regulate chromatin-modifying enzymes, thereby converting metabolic signals into epigenetic responses. For instance, enhanced glycolytic activity may increase acetyl-CoA and lactate availability, favoring chromatin states that support inflammatory and adaptive gene programs. In contrast, accumulation of succinate or fumarate may suppress α-ketoglutarate-dependent dioxygenases, disturbing normal DNA and histone demethylation. Altered one-carbon metabolism may also modify the SAM/SAH balance and consequently affect methylation-dependent gene regulation. These mechanisms can create a feedback loop in which metabolic dysfunction promotes epigenetic remodeling, while altered gene expression further reinforces abnormal metabolism. Such persistent metabolic–epigenetic interactions may contribute to chronic inflammation, uncontrolled cellular proliferation, and disease progression. Defining these metabolite–epigenetic pathways may therefore help identify new mechanisms for disease intervention and biomarker development.
• Keywords: Metabolite-Driven Epigenetic Regulation, Histone Acylation, DNA Methylation, Human Disease