ACSS2: A Metabolic Switch Driving HBV-Related Hepatocellular Carcinoma via Epigenetic Activation of Mitophagy
What's the discovery?
Our study reveals a novel metabolic-epigenetic axis crucial for Hepatitis B Virus (HBV)-related Hepatocellular Carcinoma (HCC) progression. We found that acetyl-CoA synthetase 2 (ACSS2) is specifically upregulated in HBV-related HCC, driven by the transcription factor ChREBP. This enzyme funnels acetate into a significantly elevated acetyl-CoA pool. The surplus acetyl-CoA acts as a substrate to boost histone H3 lysine 27 acetylation (H3K27ac), an activating epigenetic mark. This increase in H3K27ac, particularly on the promoter of the gene VDAC1, enhances its expression. VDAC1, a mitochondrial gatekeeper, subsequently promotes mitophagy—the selective clearance of damaged mitochondria. This enhanced mitophagy supports tumor cell proliferation and survival.
Why does it matter?
Solves a Contradiction: It clarifies previous conflicting reports on acetyl-CoA levels in HCC by identifying HBV infection as the key variable driving its specific elevation.
Links Metabolism & Epigenetics: It establishes a direct mechanistic link from viral-induced metabolic reprogramming (ACSS2 upregulation) through epigenetic modification (H3K27ac) to a key cellular process (mitophagy) in cancer.
Highlights a Precision Target: ACSS2 emerges as a specific metabolic vulnerability for HBV-related HCC, a prevalent and aggressive subtype with limited targeted options. Both genetic silencing and pharmacological inhibition of ACSS2 robustly suppressed tumor growth in models.
Clinical Translational Potential: ACSS2 expression correlates with poor patient prognosis, positioning it as a potential biomarker. Importantly, our preclinical evidence supports the exploration of existing ACSS2 inhibitors (some already in clinical trials for other cancers) for HBV-HCC therapy.
ACSS2-mediated acetyl-CoA accumulation promotes mitophagy and tumor growth via increased H3K27ac in HBV-related HCC
Shan Li, Jie Hu, Yihan Yan, Xinrui Liu, Xiao Dong, Huijun Liang, Xin Tang, Junji Tao, Rong Zhang, Yuan Hu, Ailong Huang, Kai Wang , Ni Tang
Abstract
Background/Aims： Acetyl coenzyme A (acetyl-CoA) is one of the most essential metabolites in cell metabolism but its function and concentration in hepatocellular carcinoma (HCC) remains elusive and controversial.
Methods：A comprehensive analysis of acetyl-CoA levels and ACSS2 expression across a range of samples, including patient specimens from both HBV positive and HBV negative HCC individuals, HBV-transgenic mouse HCC models, and multiple cell lines. Furthermore, to evaluate the functional significance of ACSS2 in HBV-related HCC, we implemented both genetic and pharmacological inhibition strategies targeting ACSS2. Molecular mechanism and mitophagy assessment were revealed by CUT &Tag, RNA sequencing, bioinformatic analyses, transmission electron microscopy (TEM) and JC-1 staining.
Results：Our study revealed a distinct metabolic signature of HBV-related HCC, marked by elevated acetyl-CoA, which was driven by acetyl-CoA synthetase 2 (ACSS2). ACSS2 was upregulated by the carbohydrate response element-binding protein (ChREBP) in HBV-related HCC. Furthermore, ACSS2 improved tumor cell proliferation, an effect that was dependent on its enzymatic activity. Mechanistically, ACSS2-induced acetyl-CoA accumulation activated voltage-dependent anion channels 1 (VDAC1) transcription through increased H3K27ac occupancy, which subsequently promoted mitophagy and HBV-related HCC tumorigenesis. Notably, targeting ACSS2 by depletion or inhibition with a catalytic inhibitor significantly suppressed tumor growth.
Conclusions：These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-associated HCC.
Keywords: #Liver Cancer #HCC #Hepatitis B #HBV #Metabolism #Acetyl-CoA #ACSS2 #Epigenetics #H3K27ac #Mitophagy #VDAC1 #Cancer Research #Therapeutic Target #Precision Oncology
DOI: https://doi.org/10.3350/cmh.2025.0754
Full text: https://www.e-cmh.org/journal/view.php?doi=10.3350/cmh.2025.0754
