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
Annual Review of Pathology: Mechanisms of Disease
.2026; 21(1): 185. CrossRef
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
Overexpression of S100 Calcium-Binding Protein A2 is Associated With Poor Prognosis in Hepatocellular Carcinoma Xiaopeng Chen, Shaoqing Ma, Wenlong Zeng, Chuiguo Huang, Jianyang Guo Cancer Control.2026;[Epub] CrossRef
Correspondence to letter to the editor 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(2): e241. CrossRef
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
Clinical applications of immunogenomics in hepatocellular carcinoma James K. Carter, Daniel C. Cameron, Augusto Villanueva Clinical and Molecular Hepatology.2026; 32(2): 511. CrossRef
Unveiling the Intricate Dance: Signaling Pathways in Liver Cancer Metabolism and Immunity Yichi Xu, Bo Wen, Dai Zhang, Fangxin Tang, Shu Liu Current Oncology Reports.2026;[Epub] CrossRef
First
Prev
