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
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
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.
Results 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
Citations to this article as recorded by
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
A novel link between tumor cell metabolism and patient prognosis: Editorial 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): 420. CrossRef
Zonation, Zonation, Zonation: The Real Estate of the Liver Tyler M. Yasaka, Chang Kyung Kim, Vik Meadows, Satdarshan P. Monga
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Critical flaws in the molecular classification of HCC based on metabolic zonation: Letter to the editor on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway” Yongzhi Xie, Xiangyu Zhu, Qi Liang Clinical and Molecular Hepatology.2026; 32(2): e144. CrossRef
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Correspondence to editorial on “UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL” Renyu Zhang, Ding Wei, Zhinan Chen, Huijie Bian Clinical and Molecular Hepatology.2025; 31(1): e58. CrossRef
Background/Aims Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking.
Methods Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth.
Results Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy.
Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.
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