Background/Aims Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications.
Result s: Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The “rich metabolism” subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, wellto-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatorymicroenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32–S37) mutations, and an immune-desert/excluded phenotype. The “glycolysis” subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis.
Conclusions The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity.
Citations
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Correspondence to editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway” Tomoko Aoki, Naoshi Nishida, Masatoshi Kudo Clinical and Molecular Hepatology.2026; 32(1): e79. CrossRef
Molecular stratification of hepatocellular carcinoma by metabolic-signaling pathways guides precision immunotherapy and TACE therapy Binghua Li, Yanchao Xu, Yican Zhu, Yukun Zhang, Zijie Wu, Tianci Luo, Laizhu Zhang, Weiwei Hu, Decai Yu Clinical and Molecular Hepatology.2026; 32(1): e16. CrossRef
Reply to correspondence on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway” Eun Ji Jang, Pil Soo Sung Clinical and Molecular Hepatology.2026; 32(1): e115. CrossRef
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Single-cell RNA sequencing and spatial transcriptomic analysis reveal a distinct population of G6PD+ cells with aberrant bile acid metabolism in hepatocellular carcinoma Xing Jiang, Haiyan Quan, Ting Yin, Hailun Yao, Yajun Li, Bin Peng, Xinye Yuan, Weiguang Zeng, Honghui Chen, Rong Li Frontiers in Immunology.2026;[Epub] CrossRef
Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography: A Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in Hepatocellular Carcinoma Masatoshi Kudo Liver Cancer.2025; 14(5): 511. CrossRef
Early portal hypertension in metabolic dysfunction-associated steatotic liver disease: a concise review Iván López-Méndez, Eva Juárez-Hernández, Juan Pablo Soriano-Márquez, Misael Uribe, Graciela Castro-Narro Expert Review of Gastroenterology & Hepatology.2025; 19(7): 755. CrossRef
The effects of next generation probiotics on metabolic dysfunction-associated steatotic liver disease: a parallel, double-blind, randomized, placebo-controlled trial Sung-Min Won, Hyunchae Joung, In Gyu Park, Sang Hak Han, Young Lim Ham, Ji Sook Han, Yoojin Kwon, Dong Joon Kim, Ki Tae Suk Journal of Translational Medicine.2025;[Epub] CrossRef
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Background/Aims It has been acknowleged that diverse factors such as Hepatitis B or C virus, alcohol, food carcinogens, and environmental or genetic factors are involved in hepatocellular carcinogenesis. In the molecular biologic aspect, suppression of tumor suppressor gene or amplification of oncogene, abnormal regulation of cell cycle-related proteins, abnormal apoptosis mechanism, and diverse growth factors are reported to be factors that contribute to hepatocellular carcinogenesis. In this study, the genetic difference between hepatocellular carcinoma tissue and surrounding non-hepatocellular carcinoma tissue has been investigated to identify genes that are deleted, diminished, amplified, or newly developed in hepatocellular carcinoma using differential gene expression.Method:We studied each of 12 biopsy samples of hepatocellular carcinoma and surrounding non-hepatocellular carcinoma tissues obtained during surgical resections. Random arbitrarily primed-polymerase chain reaction(RAP-PCR) was applied for differential gene expression. The genes that are deleted, diminished, or amplified, newly developed in hepatocellular carcinoma are cloned, sequenced, and then identified by BLAST search, some genes are characterized by eletrophoresis motility shift assay(EMSA) and in situ hybridization. Results:We identified the various, diverse genes classified as tumor suppressor genes, oncogenes, growth factor genes, and some kinds of transcription factors. Some of these genes were identified to be repressed, deleted or diminished, others were amplified, or newly developed in hepatocellular carcinoma tissues.Conclusions:RAP-PCR is a good method in the identification of the gene associated with hepatocellular carcinoma. The result in this study shows that so many genes are different between hepatocellular carcinoma and surrounding non- hepatocellular carcinoma tissues, and that the genes related with hepatocellular carcinogenesis may be predicted. Further studies are necessary for analyzing the relationship between the identification of the gene associated with hepatocellular carcinoma and the diverse factors involved in hepatocellular carcinogenesis.
(Korean J Hepatol 2001;7:265-272)
Oromucosal cytokine therapy allows large amounts of cytokines to be administered with improved outcome and without dose limiting toxicity. Orally administered cytokines exert their effects by a novel two pronged mechanism of action. Firstly, specific populations of immuno-competent effector cells are activated in the oral cavity and migrate to the site of virus replication. Secondly, chemokines produced in the lymphoid tissue of the oral cavity enter the peripheral circulation and redirect activated lymphocytes to eliminate virus infected cells. Oromucosal IFN therapy constitutes an alternative and improved means of therapy for diseases such as chronic viral hepatitis which are currently treated parenterally with IFNα. The oral route also has obvious advantages for ease of administration and improved patient compliance. Furthermore, the availability of a well tolerated form of IFN therapy will also allow Type I IFNs to be used for the treatment of diseases such as upper respiratory tract virus infections, for which parenteral IFN therapy is currently precluded due to unacceptable toxicity.(Korean J Hepatol 2002;8:125-131)
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