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) remain elusive and controversial.
Methods A comprehensive analysis of acetyl-CoA levels and acetyl-CoA synthetase 2 (ACSS2) expression across a range of samples, including patient specimens from both hepatitis B virus (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 cleavage under target and tagmentation sequencing, RNA sequencing, bioinformatic analyses, transmission electron microscopy 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 ACSS2. ACSS2 was upregulated by the carbohydrate response element-binding protein 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 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-related HCC.
Citations
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From metabolites to chromatin: ACSS2-driven acetyl-CoA fuels H3K27ac chromatin remodeling in HBV-associated HCC: Editorial on “Acetyl-coenzyme A synthetase 2-mediated acetyl-coenzyme A accumulation promotes mitophagy and tumor growth via increased H3K27ac Hyeong-Jin Cho, Sung-Gyoo Park Clinical and Molecular Hepatology.2026; 32(3): 1444. CrossRef
Metabolic Reprogramming at the Tumor–Immune Interface in Hepatocellular Carcinoma Weiming Zhao, Ping Li Cells.2026; 15(15): 1357. CrossRef
Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities Jingyi Cheng, Ting Xiao, Zhangui Tang, Yuhan Chen Free Radical Biology and Medicine.2026; 255: 573. CrossRef
Metabolic-epigenetic regulation of the HBV cccDNA reservoir: pathways underpinning viral persistence Qing Peng, Liyuan Hao, Shenghao Li, Fei Yu, Na Li, Fanghang Ye, Xiaoyu Hu Frontiers in Microbiology.2026;[Epub] CrossRef
Background/Aims The role of reactivation of human cytomegalovirus (HCMV) in determining outcomes of cirrhotic patients with acute decompensation (AD) is unknown. We aimed to investigate HCMV incidence and potential correlation with hepatic outcomes in AD patients.
Methods Two prospective multicentre cohorts with AD patients were investigated. Patients in cohort 1 were recruited from 4 centres, while patients in cohort 2 were randomly selected from a second multicentre cohort. HCMV reactivation was established with quantitative real-time polymerase chain reaction assay in seropositive patients.
Results HCMV reactivation was found in 35 patients from cohort 1 (n=722) and 14 from cohort 2 (n=291), with an incidence of 4.8% in both cohorts. Bacterial infection and liver failure were independently correlated with HCMV reactivation. HCMV reactivation was an independent predictor of 90-day mortality. Among bacterial infection populations in these two cohorts, patients with HCMV reactivation had worse prognosis compared to those without. Incidence of acute-on-chronic liver failure (ACLF) was higher in patients with HCMV reactivation compared to those without and was also independently correlated with development of ACLF. In a total of 49 HCMV reactivation cases, 8 patients were treated with ganciclovir, in whom a significantly lower 90-day mortality compared with those not treated was observed. All 3 patients who underwent liver transplantation with reactivation of HCMV died.
Conclusions In AD patients, HCMV reactivation was common, especially in those with bacterial infection or liver failure, and they were more prone to having ACLF and 90‑day mortality. The data propose the need for active surveillance for HCMV infection in AD patients.
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Human cytomegalovirus reactivation in decompensated cirrhosis: marker of immunosuppression or contributor to severity?: Editorial on “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation” Zhujun Cao, Richard Moreau Clinical and Molecular Hepatology.2026; 32(2): 953. CrossRef
Correspondence to editorial on “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation” Changze Hong, Jinjun Chen Clinical and Molecular Hepatology.2026; 32(2): e227. CrossRef
Call for preemptive treatment of cytomegalovirus in patients with cirrhosis and acute decompensation: Editorial on “Human cytomegalovirus reactivation in cirrhosis patients with acute decompensation” Norihiro Imai Clinical and Molecular Hepatology.2026; 32(2): 949. CrossRef
Gestational and Congenital Toxoplasmosis: An Updated Review with Emphasis on High-Prevalence Countries Alan Roberto Hatanaka, Antonio Braga, Evelyn Traina, Larissa Keren de Azevedo Teixeira, Carolina Longo, Pedro Teixeira Castro, Heron Werner, Gustavo Yano Callado, Edward Araujo Júnior Women.2026; 6(3): 43. CrossRef
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