ACSS2-mediated acetyl-CoA accumulation promotes mitophagy and tumor growth via increased H3K27ac in HBV-related HCC
Shan Li（李善）, Jie Hu（胡杰）, Yihan Yan（闫艺涵）, Xinrui Liu（刘鑫瑞）, Xiao Dong, Huijun Liang, Xin Tang, Junji Tao, Rong Zhang, Yuan Hu*, Ailong Huang*, Kai Wang*, Ni Tang*,
摘要
背景 与目的 乙酰辅酶A（acetyl-CoA）是细胞代谢中最核心的代谢产物之一，但其在肝细胞癌（HCC）中的功能和浓度仍不明确且存在争议 。
方法 研究者对一系列样本进行了乙酰辅酶A水平和乙酰辅酶A合成酶2（ACSS2)表达的全面分析，这些样本包括乙肝病毒（HBV）阳性和阴性HCC患者的标本、HBV转基因小鼠HCC模型以及多种细胞系 。此外，为了评估ACSS2在HBV相关肝癌中的功能意义，研究采用了针对ACSS2的遗传学抑制和药理学抑制策略 。通过CUT&Tag、RNA测序、生物信息学分析、透射电子显微镜（TEM）和JC-1染色，揭示了其分子机制并对线粒体自噬进行了评估 。
结果 研究揭示了HBV相关肝癌具有独特的代谢特征，其表现为乙酰辅酶A水平升高，而这一过程是由乙酰辅酶A合成酶2（ACSS2）驱动的 。在HBV相关肝癌中，ACSS2受转录因子——碳水化合物反应元件结合蛋白（ChREBP）的上调 。此外，ACSS2能够促进肿瘤细胞增殖，且该作用依赖于其酶活性 。从机制上讲，ACSS2诱导的乙酰辅酶A积累通过增加H3K27ac的富集，激活了电压依赖性阴离子通道1（VDAC1）的转录，进而促进了线粒体自噬和HBV相关肝癌的发生 。值得注意的是，通过基因敲除或使用催化抑制剂靶向ACSS2，可显著抑制肿瘤生长 。
结论 这些发现不仅阐明了在HBV感染背景下，代谢重编程、表观遗传修饰与肿瘤发生之间的相互作用，还凸显了ACSS2是HBV相关肝癌中一个新的代谢脆弱点 。因此，靶向ACSS2可能成为抗乙肝相关肝癌的一种新策略 。
关键词： 肝癌；乙型肝炎病毒；乙酰辅酶A；组蛋白乙酰化；线粒体自噬
全文链接： https://www.e-cmh.org/journal/view.php?doi=10.3350/cmh.2025.0754
乙型肝炎病毒感染通过代谢重编程促进肝癌进展的新机制
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; Hepatitis B virus; Acetyl-CoA; Histone acetylation; Mitophagy
DOI：10.3350/cmh.2025.0754
Link: https://www.ncbi.nlm.nih.gov/pubmed/41414763/