Hepatocellular Carcinoma Research Finds Link Between Epigenetic Regulation and Metabolic Reprogramming

Hepatocellular Carcinoma (HCC) remains the most common form of primary liver cancer, with high mortality rates and limited effective treatments. HCC cells undergo extensive metabolic reprogramming, including alterations in glucose, lipid, and amino acid metabolism, to support rapid proliferation and survive in harsh tumour microenvironments. At the same time, widespread changes occur in the epigenetic landscape, involving DNA methylation, RNA methylation, non-coding RNA dysregulation, and histone modifications. Although each process has been studied in depth, their intricate interplay has only recently emerged as a critical driver of hepatocarcinogenesis.

Professor Kefei Yuan and his team at West China Hospital, Sichuan University, in China, conducted a systematic review of the latest research on this interaction. Their review was published online in the Chinese Medical Journal on 30th July 2026.

“A thorough understanding of how epigenetic modifications and metabolic reprogramming interact in HCC is critical for elucidating the mechanisms underlying hepatocarcinogenesis and developing new treatment approaches against HCC,” explains Professor Yuan, the corresponding author of the review. “In this article, we systematically introduce the molecular basis of each epigenetic modification, then summarise the latest research progress on epigenetic regulation of metabolism in HCC, trying to link these two frontier fields.”

The review outlines five major types of epigenetic modifications and their roles in metabolic reprogramming.

DNA methylation shows bidirectional crosstalk with multiple metabolic pathways. Aberrant methylation of metabolic gene promoters drives changes in glycolysis, lipid synthesis, and amino acid metabolism. Conversely, metabolic intermediates such as S-Adenosylmethionine (SAM), a metabolite produced through one-carbon metabolism, provide methyl groups for DNA methylation, creating a feedback loop.

RNA methylation, particularly N6-methyladenosine (m6A), fine-tunes the expression of metabolic enzymes. This process involves “writers” (e.g., METTL3), “erasers” (e.g., FTO), and “readers” (e.g., YTHDFs, IGF2BPs). This dynamic regulation controls key processes, including glycolysis, lipid synthesis, and amino acid metabolism.

Non-coding RNAs form a multilayered regulatory network. MicroRNAs directly target metabolic enzyme mRNAs. Circular RNAs act as miRNA sponges or encode functional peptides. Long non-coding RNAs interact with proteins, remodel chromatin, or stabilise metabolic enzymes to influence metabolic pathways in HCC.

Histone modifications such as methylation, acetylation, lactylation, phosphorylation, and ubiquitination integrate metabolic signals into transcriptional programmes. Histone acetylation relies on acetyl-CoA derived from glucose and lipid metabolism, while histone methylation depends on SAM from amino acid metabolism. Emerging modifications such as lactylation link glycolysis directly to gene regulation.

RNA editing, predominantly adenosine-to-inosine (A-I) editing mediated by ADAR1, contributes to metabolic reprogramming by altering key genes involved in polyamine metabolism and oxidative stress responses.

The review highlights the link between epigenetics and metabolism as a promising therapeutic target. Preclinical studies have shown that targeting DNA methyltransferases, histone modifiers, or non-coding RNAs can reverse metabolic reprogramming and suppress tumour growth. For instance, inhibitors of DNMT1 and histone methyltransferases have demonstrated anti-tumour effects in HCC models, while nanoparticle-mediated delivery of siRNAs targeting metabolic enzymes has shown efficacy in reducing tumour burden.

“Given that epigenetic mechanisms drive metabolic reprogramming essential for HCC survival and drug resistance, targeting this axis theoretically could overcome chemoresistance,” notes Professor Yuan. “However, promising preclinical candidates have not yet advanced to clinical trials, underscoring the need for further interdisciplinary research.”

The authors note that despite significant progress, several questions remain unresolved. The specific effects of metabolites such as cholesterol, ethanol, and α-ketoglutarate on DNA methylation require further exploration. The relationship between histone modifications and amino acid metabolism remains unclear. Additionally, the role of ketone body metabolism in histone acetylation and the involvement of histone demethylases in metabolic reprogramming warrant further investigation.

This reciprocal crosstalk between metabolism and epigenetics enhances the malignant characteristics of HCC and helps create a tumour-promoting microenvironment. By connecting these fields, the review provides a clearer framework for understanding HCC development and may inform future treatment strategies.