Clinical and Molecular Hepatology

"Molecular"

Review

Stratifying cholangiocarcinoma: tumor microenvironment, molecular drivers, and novel immunotherapeutic approaches: Cindy Xinqi Liu, Carmen Chak-Lui Wong; Clin Mol Hepatol 2026;32(1):127-155.
Published online October 14, 2025; DOI: https://doi.org/10.3350/cmh.2025.0889

Abstract
PDF

Cholangiocarcinoma (CCA) is an epithelial cell cancer of the biliary tract. CCA can be further classified into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA) depending on the anatomical location. Until recently, the treatment for advanced CCA has remained highly reliant on chemotherapy, with gemcitabine plus cisplatin used in first-line treatment. Recent developments have led to the addition of immune checkpoint blockade (ICB) to the chemotherapy regimen, highlighting the promising potential of immunotherapies for CCA treatment. Despite these developments, most patients still do not benefit from current treatments, and response rates to ICB monotherapy remain modest. This underscores the need to develop more effective immunotherapeutic strategies. A major obstacle to this is the highly heterogenous nature of the disease. CCA tumors exhibit high inter-tumor heterogeneity in terms of anatomical locations, driver mutations, etiologies, and tumor microenvironment (TME) composition, making each patient immunologically distinct and difficult to benefit from a one-size-fits-all approach. There is a need to stratify patients according to individual disease status to identify immunotherapies and combination therapies that are most beneficial to them. Here we describe the different ways inter-tumor heterogeneity may arise in CCA, including stromal cell abundance, anatomical location, driver mutations, etiologies, TME profile, and tertiary lymphoid structure (TLS) presence. We also discuss what these factors mean to the immune microenvironment and their potential to be used as biomarkers. Careful stratification of patients is crucial in designing personalized medicine to improve survival outcomes and treatment efficacy for CCA patients.

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Integrative single-cell and machine-learning analysis identifies ac4C-related S100A13 as a causal risk gene in cholangiocarcinoma
Yi Zheng, Yan Lin, Zilin Wang, Fazong Wu
BMC Cancer.2026;[Epub] CrossRef
Development of a prediction model integrating cardiac ultrasound parameters for cardiac complications after distal cholangiocarcinoma surgery: a retrospective cohort study
Fangfei Wang, Shan Jin, Shaocheng Lyu, Xin Zhao, Xiuzhang Lyu, Qiang He
BMC Medical Imaging.2026;[Epub] CrossRef
Combined Model of Inflammatory-Nutritional Indicators and Tumor Markers for Predicting Prognosis in Patients with Distal Cholangiocarcinoma: A Retrospective Cohort Study
Fangfei Wang, Jinhao Li, Xin Zhao, Shaocheng Lyu, Qiang He
Diseases.2026; 14(3): 97. CrossRef

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Correspondence

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; Clin Mol Hepatol 2026;32(2):e241-e243.
Published online July 14, 2025; DOI: https://doi.org/10.3350/cmh.2025.0760

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Letter to the Editor

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; Clin Mol Hepatol 2026;32(1):e16-e20.
Published online May 8, 2025; DOI: https://doi.org/10.3350/cmh.2025.0344

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The survival prognosis after adjuvant transcatheter arterial chemoembolization in primary liver cancer: Aretrospective study
Zhangjun Chen, Chang Lin, Jie Zhang
Current Problems in Surgery.2025; : 101811. CrossRef
S100A9 promotes resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma by degrading PARP1 and activating the STAT3/PD-L1 pathway
Xianwei Zhou, Chu Qiao, Xuehui Chu, Yajing Yang, Haoran Man, Jingxin Liu, Yunzheng Li, Zhu Xu, Huan Li, Xiaodong Shan, Zaowu Lian, Yanjun Lu, Weihong Wang, Decai Yu, Xitai Sun, Binghua Li
Cellular Oncology.2025; 48(5): 1433. CrossRef

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Editorials

Hepatic neoplasm

Genetic insights into sarcomatoid hepatocellular carcinoma: Critical role of ARID2 in pathogenesis and immune feature: Editorial on “Integrated molecular characterization of sarcomatoid hepatocellular carcinoma”: Naoshi Nishida; Clin Mol Hepatol 2025;31(2):635-639.
Published online January 24, 2025; DOI: https://doi.org/10.3350/cmh.2025.0071

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Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma
Hideki Iwamoto, Hironori Koga, Takumi Kawaguchi
Clinical and Molecular Hepatology.2026; 32(1): e38. CrossRef
Correspondence to editorial on “Integrated molecular characterization of sarcomatoid hepatocellular carcinoma”
Rong-Qi Sun, Shao-Lai Zhou
Clinical and Molecular Hepatology.2025; 31(2): e192. CrossRef
Curative response to combined targeted-immunotherapy for post-hepatectomy lymph node metastasis in sarcomatoid hepatocellular carcinoma: case report and literature review
Pan Liu, Song Zhang, Xiao-Ming Xin, Min Jing, Lie-Dong Wen, Xin Xiang, Shun-Hai Liu
Frontiers in Oncology.2025;[Epub] CrossRef

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Hepatic neoplasm

Transcriptomic signature in advanced hepatocellular carcinoma tissue to predict combination immunotherapy response: Editorial on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Hiroaki Kanzaki, Yujin Hoshida; Clin Mol Hepatol 2025;31(1):308-310.
Published online August 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.0726

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Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee
Clinical and Molecular Hepatology.2025; 31(1): e81. CrossRef
Advances and challenges in immunotherapy and molecular imaging for hepatocellular carcinoma
Tu Haibin
Discover Oncology.2025;[Epub] CrossRef

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Review

Hepatic neoplasm

Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Japanese perspective: Hironori Koga, Hideki Iwamoto, Hiroyuki Suzuki, Shigeo Shimose, Masahito Nakano, Takumi Kawaguchi; Clin Mol Hepatol 2023;29(2):242-251.
Published online March 20, 2023; DOI: https://doi.org/10.3350/cmh.2023.0102

Abstract
PDF

Striking advances in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) have improved the average prognosis of patients with HCC. As a result, the guidelines for the treatment of HCC have changed significantly. However, various issues have emerged in clinical practice. First, there is no established biomarker that can predict response to systemic therapy. Second, there is no established treatment regimen after primary systemic therapy, including combined immunotherapy. Third, there is no established treatment regimen for intermediate-stage HCC. These points make the current guidelines ambiguous. In this review, we present the Japanese guidelines for the diagnosis and treatment of HCC based on the latest evidence; introduce various efforts mainly in Japanese real-life practice to update these guidelines; and present our perspectives on future guidelines.

Citations

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Editorial

Hepatic neoplasm

Management of hepatocellular carcinoma in China: Seeking common grounds while reserving differences: Tian Yang, Ming-Da Wang, Xin-Fei Xu, Chao Li, Han Wu, Feng Shen; Clin Mol Hepatol 2023;29(2):342-344.
Published online March 16, 2023; DOI: https://doi.org/10.3350/cmh.2023.0106

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Reviews

Hepatic neoplasm

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity: Hideki Iwamoto, Shigeo Shimose, Tomotake Shirono, Takashi Niizeki, Takumi Kawaguchi; Clin Mol Hepatol 2023;29(3):593-604.
Published online February 13, 2023; DOI: https://doi.org/10.3350/cmh.2022.0391

Abstract
PDF

Recently, treatments for unresectable hepatocellular carcinoma (HCC) have undergone remarkable development. Various systemic chemotherapy drugs have been approved and are recommended by clinical guidelines worldwide. Although systemic treatments are effective and contribute to prolonged patient survival, their effects are unsatisfactory for some specific tumor conditions, such as macrovascular invasion. Hepatic arterial infusion chemotherapy (HAIC) is a traditional treatment for advanced HCC. As yet, there is no worldwide consensus recommending HAIC because no high-quality clinical trials have demonstrated its survival benefit. However, clinical evidence is gradually accumulating that shows its survival benefit, and it is recognized as an effective locoregional treatment for advanced HCC. Several HAIC regimens have been reported, including cisplatin monotherapy, cisplatin plus 5-fluorouracil (low-dose FP), lipiodol-suspended FP, and an oxaliplatin-based regimen. We have entered an era of chemo-diversity in the treatment of advanced HCC. This review aimed to clarify the relevance of HAIC in the era of chemo-diversity. We propose a multidisciplinary therapeutic strategy combining locoregional HAIC treatment with sequential drug therapy, with the aim of becoming cancer-free through conversion therapy.

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Guanhui Li, Xuefei Zhao, Jie Long, Yi Li, Zhexuan Ye, Lili Rao, Yuqin He, Shujie Lai, Yuxin Tang, Hao Zhong, Chao Li, Jie Li, Changxu Cai, Hao Wu, Xiang Lan, Nan You, Jun Wang, Liangzhi Wen
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Journal of Hepatocellular Carcinoma.2026; Volume 13: 1. CrossRef
DEB-TACE-HAIC combined with donafenib and camrelizumab in the treatment of unresectable hepatocellular carcinoma: a multicenter retrospective study
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Deep learning-based prediction of molecular cancer biomarkers from tissue slides: A new tool for precision oncology: Sung Hak Lee, Hyun-Jong Jang; Clin Mol Hepatol 2022;28(4):754-772.
Published online April 21, 2022; DOI: https://doi.org/10.3350/cmh.2021.0394

Molecular tests are necessary to stratify cancer patients for targeted therapy. However, high cost and technical barriers limit the application of these tests, hindering optimal treatment. Recently, deep learning (DL) has been applied to predict molecular test results from digitized images of tissue slides. Furthermore, treatment response and prognosis can be predicted from tissue slides using DL. In this review, we summarized DL-based studies regarding the prediction of genetic mutation, microsatellite instability, tumor mutational burden, molecular subtypes, gene expression, treatment response, and prognosis directly from hematoxylin- and eosin-stained tissue slides. Although performance needs to be improved, these studies clearly demonstrated the feasibility of DL-based prediction of key molecular features in cancer tissues. With the accumulation of data and technical advances, the performance of the DL system could be improved in the near future. Therefore, we expect that DL could provide cost- and time-effective alternative tools for patient stratification in the era of precision oncology.

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Hepatic neoplasm

Optimizing the management of intermediate-stage hepatocellular carcinoma: Current trends and prospects: Takuji Torimura, Hideki Iwamoto; Clin Mol Hepatol 2021;27(2):236-245.
Published online December 3, 2020; DOI: https://doi.org/10.3350/cmh.2020.0204

Abstract
PDF

Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.

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Special topic: Alcoholic liver diseases
The 14th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis (ISALPDC)

Alcohol-related liver disease

Roles of the complement system in alcohol-induced liver disease: Yi Zhou, Guandou Yuan, Fudi Zhong, Songqing He; Clin Mol Hepatol 2020;26(4):677-685.
Published online October 1, 2020; DOI: https://doi.org/10.3350/cmh.2020.0094

Abstract
PDF

Alcohol-induced liver disease (ALD) is a complex disorder, with a disease spectrum ranging from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although the pathogenesis of ALD is incompletely understood and currently no effective drugs are available for ALD, several lines of evidence suggest that complement activation and oxidative stress play crucial roles in the pathogenesis of ALD. Complement activation can regulate the production of ROS and influence oxidative stress in ALD. Precise regulation of the complement system in ALD may be a rational and novel avenue to postpone and even reverse the progression of disease and simultaneously promote the repair of liver injury. In this mini-review, we briefly summarize the recent research progress, especially focusing on the role of complement and oxidative stress-induced transfer RNA-derived fragments, which might help us to better understand the pathogenesis of ALD and provide aid in the development of novel therapeutic strategies for ALD.

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Reviews

Hepatitis C virus and hepatocarcinogenesis: Soung Won Jeong, Jae Young Jang, Raymond T. Chung; Korean J Hepatol 2012;18(4):347-356.
Published online December 21, 2012; DOI: https://doi.org/10.3350/cmh.2012.18.4.347

Abstract
PDF

Hepatitis C virus (HCV) is an RNA virus that is unable to integrate into the host genome. However, its proteins interact with various host proteins and induce host responses. The oncogenic process of HCV infection is slow and insidious and probably requires multiple steps of genetic and epigenetic alterations, the activation of cellular oncogenes, the inactivation of tumor suppressor genes, and dysregulation of multiple signal transduction pathways. Stellate cells may transdifferentiate into progenitor cells and possibly be linked to the development of hepatocellular carcinoma (HCC). Viral proteins also have been implicated in several cellular signal transduction pathways that affect cell survival, proliferation, migration and transformation. Current advances in gene expression profile and selective messenger RNA analysis have improved approach to the pathogenesis of HCC. The heterogeneity of genetic events observed in HCV-related HCCs has suggested that complex mechanisms underlie malignant transformation induced by HCV infection. Considering the complexity and heterogeneity of HCCs of both etiological and genetic aspects, further molecular classification is required and an understanding of these molecular complexities may provide the opportunity for effective chemoprevention and personalized therapy for HCV-related HCC patients in the future. In this review, we summarize the current knowledge of the mechanisms of hepatocarcinogenesis induced by HCV infection.

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Molecular targeting for treatment of advanced hepatocellular carcinoma: Il Han Song; Korean J Hepatol 2009;15(3):299-308.
Published online September 30, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.3.299

Abstract
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Hepatocellular carcinoma (HCC) is a major global health problem, which has a grave morbidity and mortality. Over the past few decades, no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage. Sorafenib is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of Raf-1 and B-Raf serine-threonine kinases, and exerts an anti-angiogenic effect by targeting the vascular endothelial growth factor receptor-1, 2 and 3, and platelet-derived growth factor receptor-β tyrosine kinases. Recently, two clinical successful applications, SHARP and Asia-Pacific trial, of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance. However, because the results of clinical trials show diverse responses in a subset of HCC patients, a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity, ultimately leading to the most suitable individualization of molecular targeted therapy in HCC. (Korean J Hepatol 2009,15:299-308)

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Clinical Experience of Cell-free Liver Support System: Hee Jung Wang,Myung Wook Kim; Korean J Hepatol 2000;6(4):421-424.

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Wilson Disease: an Update: Jeong Kee Seo; Korean J Hepatol 2006;12(3):333-363.

Abstract
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Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (<20 mg/dL), high 24 hour urine copper (>100 μg), high hepatic copper content (>250 μg/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.

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