Hepatocellular carcinoma (HCC) cells undergo extensive metabolic reprogramming, including alterations in glucose, lipid, and amino acid metabolism, to meet the demands of rapid proliferation and survive in harsh tumor microenvironments. Simultaneously, widespread changes occur in the epigenetic landscape, such as DNA methylation, RNA methylation, non-coding RNA dysregulation, and histone modifications. While each of these processes has been studied extensively, their intricate interplay has emerged as a critical driver of hepatocarcinogenesis.
To address this gap, Professor Kefei Yuan and his team from the West China Hospital, Sichuan University, China, along with colleagues, conducted a systematic review of the latest research on the interaction between epigenetic regulation and metabolic reprogramming in HCC. Their review was published online in the Chinese Medical Journal on July 30, 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 Prof. Yuan, the corresponding author of the review. "In this article, we systematically introduce the molecular basis of each epigenetic modification, then summarize 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 connections to 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) derived from 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 through "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 multi-layered regulatory network. MicroRNAs directly target metabolic enzyme mRNAs; circular RNAs act as miRNA sponges or encode functional peptides; and long non-coding RNAs interact with proteins, remodel chromatin, or stabilize metabolic enzymes to influence metabolic pathways in HCC.
Histone modifications such as methylation, acetylation, lactylation, phosphorylation, and ubiquitination integrate metabolic signals into transcriptional programs. Histone acetylation relies on acetyl-CoA derived from glucose and lipid metabolism, while histone methylation depends on SAM from amino acid metabolism. Emerging modifications like lactylation link glycolysis directly to gene regulation.
RNA editing, predominantly adenosine-to-inosine (A-to-I) editing mediated by ADAR1, contributes to metabolic reprogramming by altering key genes involved in polyamine metabolism and oxidative stress responses.
Importantly, the review highlights that the epigenetic-metabolism axis represents a promising therapeutic target. Preclinical studies have shown that targeting DNA methyltransferases, histone modifiers, or non-coding RNAs can reverse metabolic reprogramming and suppress tumor growth. For instance, inhibitors of DNMT1 and histone methyltransferases have demonstrated anti-tumor effects in HCC models, while nanoparticle-mediated delivery of siRNAs targeting metabolic enzymes shows efficacy in reducing tumor burden.
"Given that epigenetic mechanisms drive metabolic reprogramming essential for HCC survival and drug resistance, targeting this axis theoretically could overcome chemoresistance," notes Prof. Yuan. "However, promising preclinical candidates have not yet advanced to clinical trials, underscoring the need for further interdisciplinary research."
The authors note that while significant progress has been made, 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.
