Hepatitis B virus (HBV) is a hepatotropic DNA virus that infects about 1.2 million new patients annually, contributing a major global health burden. World Health Organization (WHO) estimates that 254 million people were living with chronic HBV infection in 2022, driving liver disease such as cirrhosis and hepatocellular carcinoma (HCC) [
1]. After the HBV virion enters a hepatocyte through the host receptor protein, sodium taurocholate cotransporting polypeptide, HBV hijacks cellular DNA repair machinery to convert relaxed circular DNA into stable covalently closed circular DNA (cccDNA) [
2]. The formation of an epigenetically stable cccDNA minichromosome, assembled with host histones and regulatory proteins, renders HBV resistant to polymerase inhibitors and underlies the persistent nature of chronic HBV infection, making functional cure extremely difficult. Although nucleos(t)ide analogues and pegylated interferon effectively suppress HBV replication, current therapies rarely achieve a functional cure in patients with chronic HBV infection. Therefore, the management of HBV-associated liver disease remains a major clinical challenge.
HBV can modulate various intracellular signaling pathways, including innate immune responses, cell cycle, and metabolic reprogramming to create a virus-favorable environment [
3-
5]. Although accumulating evidence supports these HBV-mediated alterations, the molecular mechanisms underlying these effects remain poorly understood. One proposed mechanism underlying HBV-induced alterations in cellular gene expression involves host genomic and epigenomic regulation in infected hepatocytes. The following mechanisms have been suggested to mediate HBV-driven control of host gene expression, which may contribute to viral replication and disease pathogenesis.
Integration of the HBV genome can induce cellular stress and activate DNA damage response signals [
6]. Qian et al. [
7] showed that during HBV genome integration, HBV uses cellular double-strand break repair mechanisms and induces interchromosomal translocations, contributing to HCC progression. They further demonstrated that not only altered gene expression, but also copy number variation induced by HBV integration, can influence the regulation of crucial cancer genes.
There are three main CpG islands in HBV genome, and methylation of one CpG island is highly correlated with hepatocarcinogenesis. Host DNA methyltransferase (DNMT) genes normally contribute to the methylation of viral DNA and are reported to be upregulated after HBV infection [
8,
9]. Fu et al. [
9] showed that hepatitis B virus X protein (HBx) alone can upregulate DNMT3A/3B mRNA levels and silence the innate immune-related gene
SOCS1, suggesting that HBx may contribute to HCC through DNMT-mediated methylation of
SOCS1. In contrast, Vivekanandan et al. [
10] reported that HBV infection in hepatocytes upregulates DNMTs, thereby promoting methylation of viral DNA and potentially leading to aberrant methylation of host genes. These findings suggest DNA methylation could be another host defense mechanism that contributes to epigenetic silencing of cccDNA.
After cccDNA formation, there is preferential accumulation of HBV DNA in a specialized nuclear area [
11]. HBx protein binds to HBV episomes, and HBV episomes and HBx preferentially associate with actively transcribed nuclear domains of the host genome [
12]. There is evidence that the localization of HBV episomes may play a crucial role in regulating infection outcomes. Yang et al. [
13] showed that these interactions between HBV episomes and host DNA may influence not only viral transcription but also host gene transcription.
HBV cccDNA also undergoes Histone modifications. Activation marks such as H3K4me3, H3K27ac, and H3K122ac are enriched on cccDNA. On the other hand, inhibitory marks such as H3K9me3 and H3K27me3 are surprisingly underrepresented [
14]. However, Flecken et al. [
15] recently showed that although activation marks are dominant on HBV DNA, there is still heterogeneity across patients and the patterns do not exactly match those observed in
in vitro studies. Many of the chromatin-modifying enzymes that control cccDNA-associated histone modifications also function in host chromatin regulation, indicating that HBV-induced epigenetic alterations could influence host gene expression.
Taken together, many aspects of HBV-induced epigenetic regulation remain unresolved, highlighting the need for further investigation.
In the current issue of
Clinical and Molecular Hepatology, Li et al. [
16] discovered that acetyl-coenzyme A (acetyl-CoA) synthetase 2 (ACSS2) expression and acetyl-CoA levels were higher in the liver tissue of HBV-positive HCC patients than in that of HBV-negative HCC patients, suggesting a distinct metabolic feature of HBV-associated HCC. Using HBV transgenic mice and human hepatocellular carcinoma cell lines, they showed that higher ACSS2 levels were mediated by increased levels of the transcription factor carbohydrate-responsive element-binding protein in HBV-related HCC. Elevated acetyl-CoA was essential for proliferation of an HBV-producing HCC cell line and could be reversed by inhibition of ACSS2, indicating ACSS2 may be a key host factor in the progression of HBV-associated HCC. Li et al. [
16] also showed that ACSS2- mediated increases in acetyl-CoA affect hepatocytes through acetylation of host histones, especially H3K27. They performed cleavage under targets & tagmentation sequencing (CUT&Tag-seq) and RNA sequencing, found that H3K27ac peaks at the voltage dependent anion channel 1 (VDAC1) promoters were decreased in an ACSS2-depleted HCC cell line. As a major component of the outer mitochondrial membrane, upregulation of VDAC1 induced mitophagy, leading to proliferation of HBV-related HCC. Finally, they validated their findings using a small-molecule ACSS2 inhibitor in an HBV mouse model. Li et al. [
16] not only demonstrated a novel mechanism underlying HBV-related HCC, but also suggested ACSS2 inhibitor as potential therapeutic strategy for HBV-associated liver disease.
This study provides evidence that HBV is positively associated with HCC progression and proposes a novel metabolite-epigenetic axis, the “ACSS2–acetyl-CoA–H3K27ac” pathway, as a mechanism underlying HBV-related HCC. They further showed that HBV-driven metabolic changes are not merely a byproduct of infection but can function as epigenetic signals that influence mitochondrial quality control in a manner that favors tumor progression. These findings deepen our understanding of HBV-host chromatin interactions and point to the potential of metabolism-epigenetic-based combination approaches for the treatment of HBV-associated disease.
FOOTNOTES
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Authors’ contribution
H.J. Cho drafted the manuscript and S.G. Park revised and finalized it.
-
Acknowledgements
This research was supported by the Korea Health Industry Development Institute (KHIDI) (RS-2024-00335243), by National Institute of Health (NIH) research project (project No. 2025-ER1803-00), and by the National Research Foundation of Korea (NRF-2022M3A9I2017587). The authors acknowledge the use of AI-assisted technology (ChatGPT [OpenAI], GPT-5.2 Thinking, accessed January 20, 2026) for language refinement, including grammar and vocabulary suggestions. The AI was employed solely for linguistic assistance and did not contribute to the conceptualization, analysis, or interpretation of the manuscript. The authors take full responsibility for the accuracy and integrity of the content.
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Conflicts of Interest
The authors have no conflicts of interest to declare.
Abbreviations
covalently closed circular DNA
cleavage under targets & tagmentation sequencing
hepatitis B virus X protein
voltage dependent anion channel 1
World Health Organization
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