Journal of Liver Cancer

Original Articles

Enhancing non-LR-5 liver lesion diagnoses: the incremental value of serum alpha-fetoprotein and PIVKA-II for detecting hepatocellular carcinoma components: Junghoan Park, Jeong Min Lee, Rae Rim Ryu, Seok Jin Hong; Received December 15, 2025 Accepted May 26, 2026 Published online June 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.05.26 [Accepted]

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Abstract PDF: Backgrounds/Aims
To investigate whether incorporating serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) into gadoxetic acid-enhanced liver MRI improves the accuracy of differentiating hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-CC) from non-LR-5 lesions.
Methods
This retrospective study included 123 patients comprising 70 HCC, 30 ICC, and 23 cHCC-CC cases who underwent preoperative MRI and tumor marker analysis. Two abdominal radiologists independently interpreted the MRI without markers (Decision 1). Then, lesions were reclassified as HCC if either marker was elevated, regardless of the initial interpretation (Decision 2, biomarker-assisted override strategy). Outcomes included the diagnostic performance for identifying HCC versus non-HCC malignancies and distinguishing the presence of HCC components (HCC or cHCC-CC) from ICC. The McNemar’s test and Cohen’s κ compared diagnostic performance and evaluated interobserver agreement, respectively.
Results
Adding AFP and PIVKA-II (Decision 2) improved the sensitivity and accuracy of detecting HCC components from 62.4–76.3% to 81.7–90.3% (P<0.001) and 66.7–76.4% to 81.3–87.0% (P<0.001), respectively. The overall accuracy for differentiating HCC from non-HCC malignancies did not improve. However, the accuracy for detecting HCC in small tumors (<3 cm) significantly improved from 68.8–72.5% to 81.3–82.5% (P= 0.002–0.008). Interobserver agreement also increased, from moderate (κ = 0.48) to substantial (κ = 0.68) after adding tumor marker values.
Conclusions
In non-LR-5 hepatic lesions, adding AFP and PIVKA-II to MRI interpretations significantly improved the accuracy of identifying HCC components, as well as HCC detection in small tumors.

Pain, analgesic use and misconceptions in patients with hepatocellular carcinoma: a cross-sectional survey: Jina Park, Jiwon Yang, Sung Won Chung, Won-Mook Choi, Ju Hyun Shim, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Jonggi Choi; Received January 15, 2026 Accepted March 19, 2026 Published online April 29, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.19 [Epub ahead of print]

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Abstract PDF Supplementary Material: Backgrounds/Aims
Cancer-related pain remains undertreated despite established guidelines. In hepatocellular carcinoma (HCC), underlying chronic liver disease may amplify concerns regarding analgesic safety. We aimed to evaluate pain prevalence, analgesic use, pain-related perceptions, and educational needs among patients with HCC.
Methods
We conducted a cross-sectional survey of 200 adult patients with HCC receiving systemic therapy at a tertiary referral center. A 30-item questionnaire assessed pain presence and intensity using a numeric rating scale (NRS), analgesic use patterns, liver-related safety concerns, opioid-related stigma, and educational needs. Clinical characteristics, including tumor burden and liver function, were analyzed in relation to pain and perception domains.
Results
Fifty-five patients (27.5%) reported current pain (mean NRS, 3.6±2.5; mean worst pain 5.2±2.8). Among them, 31 patients (56.3%) were using analgesics; however, 51.6% reported using them only when pain became unbearable. Misconceptions regarding analgesic safety were prevalent: 70.0% believed long-term analgesic use damages the liver, 56.0% believed analgesics are unsafe with impaired liver function, 46.5% associated opioids with addiction, and 30.0% hesitated due to the term “narcotic.” These beliefs were not associated with Child-Pugh class or serum albumin level. Extrahepatic metastasis was associated with higher liver-related concern scores and a trend toward increased pain prevalence. Patients with elementary school education or less had poorer pain scale knowledge and no prior counseling.
Conclusions
Pain undertreatment and safety-related misconceptions are common in HCC and appear independent of objective liver function. Structured, proactive education, particularly for patients with untreated pain and low educational attainment, may improve pain control in this population.

Review Articles

Imaging differentiation of hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma: pitfalls and advances: Jaeseung Shin, Taek Chung, Sang Yun Ha, Hyungjin Rhee; J Liver Cancer. 2026;26(1):9-18. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.05

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Abstract PDF: Accurate non-invasive differentiation of primary liver cancers, such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA), is crucial for optimal management but challenging due to shared risk factors and overlapping imaging phenotypes. While the Liver Imaging Reporting and Data System category M effectively captures the classic targetoid appearance of large duct type iCCA, the small duct type frequently exhibits HCC-mimicking non-rim arterial phase hyperenhancement and non-peripheral washout, potentially compromising diagnostic specificity. Furthermore, cHCC-CCA presents a formidable diagnostic dilemma, existing on a continuous imaging spectrum that reflects its histologic dominance. This continuous imaging spectrum not only blurs radiologic distinctions but also complicates tissue sampling, limiting the diagnostic accuracy of core needle biopsies and highlighting the risk of misclassification. To enhance diagnostic clarity, this review highlights their key imaging hallmarks: while HCC typically shows non-rim arterial phase hyperenhancement (APHE) and non-peripheral washout, large duct iCCA displays a classic targetoid appearance with rim APHE and progressive central enhancement. Conversely, small duct iCCA often mimics HCC, and cHCC-CCA exhibits a variable spectrum depending on its predominant histologic component. Ultimately, overcoming these diagnostic pitfalls requires a rigorous, multidisciplinary approach that synthesizes imaging findings, serologic tumor markers, and clinical contexts.

The role of radiotherapy in the management of combined hepatocellular-cholangiocarcinoma: current evidence and future perspectives: Seo Hee Choi, Woong Sub Koom, Ik Jae Lee; J Liver Cancer. 2026;26(1):55-64. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.04

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Abstract PDF: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and highly aggressive hybrid malignancy characterized by a poor prognosis and high recurrence rates due to its dual histological nature. In the absence of established standard-of-care protocols, clinical management strategies are frequently extrapolated from the guidelines for its components, hepatocellular carcinoma and intrahepatic cholangiocarcinoma (iCCA). This review evaluates the evolving role of radiotherapy (RT) as an integral part of the multidisciplinary care for cHCC-CCA. Adjuvant RT may be considered for patients exhibiting high-risk pathological features, such as positive or close resection margins, lymphovascular invasion, and perineural invasion. For unresectable disease unfeasible for surgery or transarterial therapies, definitive RT using intensified doses, analogous to iCCA protocols, is employed to improve local control. High-precision modalities, particularly particle therapies such as proton or carbon ion RT, are emphasized as preferred options for delivering ablative doses while minimizing toxicity and preserving functional liver reserve. Furthermore, preliminary clinical evidence suggests a potential synergy between RT and immune checkpoint inhibitors, with reported cases demonstrating complete responses or successful conversion to curative-intent resection. While current evidence remains limited to retrospective cohorts and case series, the strategic integration of precision RT offers a rational pathway for optimizing outcomes in cHCC-CCA, necessitating further prospective validation.

Systemic therapy for combined hepatocellular-cholangiocarcinoma: a comprehensive review of chemotherapy, immunotherapy, and targeted therapy: Jung Yong Hong, Dong Hyun Sinn, Sang Yun Ha; J Liver Cancer. 2026;26(1):36-44. Published online March 5, 2026; DOI: https://doi.org/10.17998/jlc.2026.03.02

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1 Citation

Abstract PDF

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy exhibiting both hepatocytic and cholangiocytic differentiation. Since the 2019 World Health Organization (WHO) reclassification, growing molecular and clinical evidence has reshaped our understanding of this entity. However, patients with cHCC-CCA have been systematically excluded from landmark clinical trials in both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), leaving clinicians without prospective evidence to guide treatment selection. This review comprehensively evaluates the current evidence on systemic therapy for advanced cHCC-CCA, encompassing cytotoxic chemotherapy, immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors, and molecularly targeted agents. Retrospective data indicate that gemcitabine plus platinum-based chemotherapy achieves the most consistent efficacy among conventional regimens, with median overall survival of 10-16 months. ICIs demonstrate objective response rates of 20-33% with durable responses in a subset of patients, supported by the finding that approximately 57% of cHCC-CCA tumors harbor an immune-high phenotype. Nearly 25% of tumors carry potentially actionable genomic alterations, including fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and human epidermal growth factor receptor 2 (HER2) amplification. The molecular heterogeneity of cHCC-CCA, with tumors classifiable as HCC-like or CCA-like in approximately 75% of cases, provides a rational framework for personalized treatment selection. We propose an emerging molecular classification-based treatment algorithm and identify critical gaps requiring dedicated prospective investigation. For clinical settings where comprehensive genomic profiling is not feasible, we discuss a pragmatic surrogate-based approach using imaging characteristics and serum tumor markers to guide initial treatment selection. We also address post-progression treatment considerations, including phenotype-based regimen switching and the role of re-biopsy

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Curative Effect Evaluation of Targeted Therapy and Chemotherapy for Non-Resectable Combined Hepatocellular-Cholangiocarcinoma: A Systematic Review and Meta-Analysis
永豪林
Advances in Clinical Medicine.2026; 16(05): 920. CrossRef

Original Article

Liver resection versus radiofrequency ablation or transarterial chemoembolization for early multinodular BCLC-A hepatocellular carcinoma: a systematic review and meta-analysis: Maria F. F. Viana, Arthur A. Braga, Lucas B. Carvalho, Danilo C. M. S. Vasconcellos, Bianca C. M. R. Alexandrino, Felipe J. F. Coimbra; J Liver Cancer. 2026;26(1):157-168. Published online February 26, 2026; DOI: https://doi.org/10.17998/jlc.2026.02.21

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90 Downloads

Abstract PDF Supplementary Material: Backgrounds/Aims
Hepatocellularcarcinoma (HCC) is the most common form of liver cancer, with high mortality rates worldwide. The optimal treatment strategy for patients with multinodular early-stage HCC (BCLC-A) is still controversial, particularly regarding liver resection (LR), radiofrequency ablation (RFA), and transarterial chemoembolization (TACE). This meta-analysis aims to evaluate the overall survival (OS) and disease-free survival (DFS) in patients with multinodular BCLC-A HCC treated with LR compared to RFA and TACE.
Methods
A systematic literature review and meta-analysis were performed by searching PubMed, Embase, and the Cochrane Library for studies comparing LR with RFA and TACE. Pooled analyses of OS and DFS were performed using hazard ratios (HR) with 95% confidence intervals (CI).
Results
Fifteen studies, including two randomized controlled trials and 13 cohort studies, with a total of 2,869 patients, were included. LR was significantly associated with improved OS (HR, 1.38; 95% CI, 1.03-1.84; P=0.01) and DFS (HR, 2.16; 95% CI, 1.26-3.70; P=0.001) compared with RFA. Similarly, LR demonstrated superior OS (HR, 2.11; 95% CI, 1.37-3.25; P<0.0001) and DFS (HR, 2.77; 95% CI, 1.04-7.36; P=0.04) when compared with TACE. The more pronounced benefit observed for DFS likely reflects improved local tumor control achieved with surgical resection.
Conclusions
In selected patients with multinodular BCLC-A HCC and preserved liver function (predominantly Child-Pugh A or B), LR is associated with significant improvements in OS and DFS compared with RFA and TACE when liver transplantation is not feasible. These findings support reconsideration of current treatment algorithms to prioritize LR in appropriately selected candidates.

Review Articles

Immune-related adverse events in hepatocellular carcinoma: organ-specific patterns and management approaches: Sul Ki Choi, Seonjeong Woo, Hong Jae Chon; J Liver Cancer. 2026;26(1):65-82. Published online December 29, 2025; DOI: https://doi.org/10.17998/jlc.2025.12.21

2,884 Views
197 Downloads
2 Web of Science
2 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. The recent introduction of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape for advanced HCC. Combination regimens such as atezolizumab plus bevacizumab, durvalumab plus tremelimumab, and nivolumab plus ipilimumab have demonstrated significant survival improvements over conventional tyrosine kinase inhibitors and have become the new standard of care. However, ICIs can trigger immune-related adverse events (irAEs) through overactivation of the immune system, affecting multiple organs including the skin, gastrointestinal tract, liver, endocrine system, lungs, and heart. Patients with HCC frequently have underlying liver diseases such as chronic hepatitis or cirrhosis, placing them at higher risk of hepatic irAEs compared to that with other cancer types, which can markedly influence prognosis. The pathophysiology of irAEs is driven by a series of interconnected immune mechanisms, including excessive T-cell activation, disruption of immune tolerance, cytokine dysregulation, complement-mediated injury, and innate immune activation. Clinical decisions regarding the continuation, interruption, or discontinuation of ICIs, as well as the administration of corticosteroids or immunosuppressants, should be guided by the severity of toxicity. Organ-specific management strategies and multidisciplinary collaboration are essential, particularly for severe presentations. This review summarizes the incidence, mechanisms, and management strategies for ICI-related irAEs in advanced HCC, and provides practical insights for clinical decision-making.

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Response: Reassessing the Use of Nivolumab Plus Ipilimumab After Atezolizumab Plus Bevacizumab in Advanced HCC
Jung Sun Kim, Thomas Yau, Hong Jae Chon
Liver International.2026;[Epub] CrossRef
Comparative efficacy and safety of first-line treatments for advanced hepatocellular carcinoma: a Bayesian network meta-analysis
Yun Su, Tongze Cai, Jingxuan Wei, Qiuju Huang, Chun Yao, Lei Fu, Jinghui Zheng, Hongwei Guo, Xiongbin Gui
Frontiers in Immunology.2026;[Epub] CrossRef

Exploring single-cell and multi-omics technologies and their role in unraveling tumor heterogeneity of hepatocellular carcinoma: Charmi Jyotishi, Suresh Prajapati, Mansi Patel, Reeshu Gupta; J Liver Cancer. 2026;26(1):104-123. Published online December 17, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.29

2,191 Views
88 Downloads
3 Web of Science
3 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tumor heterogeneity is a major obstacle to effective treatment and is poorly understood using traditional bulk sequencing methods. This review highlights the transformative role of single-cell and multi-omics technologies in determining the cellular and molecular complexities of HCC. We summarize recent advances in single-cell transcriptomics, epigenomics, multi-omics, and spatial transcriptomics platforms, emphasizing their applications in characterizing tumor subclones, cancer-associated fibroblast-immune interactions, circulating tumor cells, and immune-resistant phenotypes. Spatial approaches have revealed the architecture of cancer stem cell niches and tertiary lymphoid structures, providing unprecedented insights into tumor organization and microenvironmental crosstalk. Although still in their early stages, clinical trials have begun to incorporate these technologies, underscoring their translational potential. Single-cell and spatial omics have reshaped HCC research by enabling high-resolution profiling of tumor ecosystems and driving the discovery of biomarkers, therapeutic targets, and strategies for patient stratification. However, high cost, technical expertise, and limited accessibility, particularly in resource-constrained settings, are major barriers to its widespread adoption. Addressing these challenges is critical for translating these powerful approaches into clinical practice and for advancing precision medicine for the treatment of liver cancer.

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The lncRNA–DNA Methylation Axis in Hepatocellular Carcinoma: Mechanisms, Epigenetic Plasticity, and Biological Implications
Lingke Meng, Lingzhu Cheng, Yuanyuan Li, Yushan Guo, Na Li
Biology.2026; 15(6): 458. CrossRef
Review Article: Biomarkers in Liver Transplantation for Hepatocellular Carcinoma: Towards Precision Medicine
Yule Ma, Huigang Li, Huan Chen, Jinxin Xu, Ziyi Ye, Yuhang Li, Xiang Wu, Jinyan Chen, Chenghao Cao, Peiru Zhang, Ruijie Zhao, Jun Li, Cheng Zhu, Jianyong Zhuo, Shengjun Xu, Xiao Xu, Di Lu
Alimentary Pharmacology & Therapeutics.2026; 64(4): 441. CrossRef
Development and Validation of a Six-Gene Signature of Myeloid Antigen Presentation Dysfunction Based on Single-Cell and Multi-Cohort Transcriptomics for Predicting Prognosis and Recurrence of Hepatocellular Carcinoma
Ye Tan, Jingxuan Xiang, Zehan Wang, Yu Wang, Aidong Chen, Qiwen Wu
Cancer Informatics.2026;[Epub] CrossRef

Original Article

PNPLA3 I148M is unrelated to HCC occurrence but associates with poorer tumor differentiation in Korean MASLD: a prospective cohort of 562 patients: Jaejun Lee, Dong Yeop Lee, Jung Hoon Cha, Hee Sun Cho, Keungmo Yang, Hyun Yang, Mi Young Byun, Seok Keun Cho, Seong Wook Yang, Si Hyun Bae, Pil Soo Sung; J Liver Cancer. 2026;26(1):147-156. Published online December 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.16

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71 Downloads

Abstract PDF Supplementary Material: Backgrounds/Aims
The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its role in hepatocellular carcinoma (HCC) development is unclear. This study examines the association between the PNPLA3 I148M variant and HCC occurrence.
Methods
A total of 562 MASLD patients, with and without HCC, were prospectively and consecutively enrolled at two universityaffiliated hospital between June 2024 and June 2025. Genomic DNA was extracted from buccal swabs or liver biopsy samples, and single nucleotide polymorphism genotyping was performed to determine the rs738409 genotype at codon 148 of PNPLA3. The histological grade of HCC was assessed using the Edmondson-Steiner (ES) grading system in patients who underwent core-needle liver biopsy.
Results
Among 474 non-HCC patients, the GG genotype was found in 39.9%, GC in 37.1%, and CC in 23.0%. In 88 HCC patients, these frequencies were 45.5%, 36.4%, and 18.2%, respectively. No significant differences in GG genotype distribution were observed between HCC and non-HCC groups (P=0.509), nor in subgroups by sex, age, obesity status, cirrhosis status, fibrosis-4 index, or liver stiffness measurement. However, among HCC patients with histological grading, the GG genotype was significantly associated with higher ES grades (P=0.0076).
Conclusions
The PNPLA3 I148M GG genotype was not significantly associated with increased HCC occurrence in Korean MASLD patients within the present cohort. Although the GG genotype is known to play a role in development and progression of MASLD, further studies are warranted to clarify its contribution to tumor initiation and dedifferentiation.

Review Article

Re-evaluating DAA therapy in active hepatocellular carcinoma: from controversy to clinical considerations: So Hyun Jeon, Jeong-Ju Yoo, Sang Gyune Kim, Young-Seok Kim; J Liver Cancer. 2026;26(1):93-103. Published online December 2, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.17

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Abstract PDF: Direct-acting antiviral (DAA) therapy has brought a revolution to the management of chronic hepatitis C virus infection, but its role in patients with active hepatocellular carcinoma (HCC) remains controversial. Early observations suggested a high rate of HCC recurrence following DAA treatment, raising concerns about a potential oncogenic effect regarding rapid viral clearance. However, subsequent large-scale cohort studies and meta-analyses have not consistently confirmed this finding, leading to an overall neutral conclusion regarding the impact of DAA on HCC recurrence. International guidelines from organizations such as the American Gastroenterological Association, American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Korean Association for the Study of the Liver offer conflicting recommendations, underscoring the absence of a universal framework for this patient population. While the available evidence is largely heterogeneous and retrospective, current data indicate that DAA therapy can be safely integrated into HCC management without clear evidence of harm. Oncologic outcomes, particularly overall and recurrence-free survival, are most favorable when DAAs are administered in close proximity to curative procedures or in non-transplant therapeutic settings. In contrast, studies in liver transplant candidates often show a neutral effect on oncologic outcomes after adjusting for confounding variables. These findings underscore the necessity of individualized, multidisciplinary decisions based on tumor biology, hepatic reserve, and treatment intent. Prospective studies and validated biomarkers are essential to establish a more definitive framework for optimizing DAA therapy in this complex clinical context.

Special Contribution

Impact of the 2024 medical-policy conflict on hepatocellular carcinoma management in Korea: Soon Sun Kim, Hyun Yang, Jieun Kwon, Eunju Kim, Jeong Il Yu, Janghan Jung, Woosun Choi, Ji Eun Han, Moon Haeng Hur, Bo Hyun Kim, Sung Hyun Kim, Jeong Han Kim, Haeryoung Kim, Pyoung-Jae Park, Hyun Phil Shin, Su Jong Yu, Ki Tae Yoon, Sang Min Yoon, Minjong Lee, Jai Young Cho, Jin-Young Choi, Do Young Kim, June Sung Lee, Mi-Sook Kim, Kyung Sik Kim; J Liver Cancer. 2025;25(2):169-177. Published online September 2, 2025; DOI: https://doi.org/10.17998/jlc.2025.09.01

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85 Downloads

Abstract PDF: In 2024, a nationwide conflict between the South Korean government and the medical community, the medical-policy conflict, profoundly impacted healthcare delivery. This study aimed to evaluate the changes in the management of hepatocellular carcinoma (HCC) following this crisis. We analyzed retrospective real-world data from university hospitals in the Seoul Metropolitan Area, supplemented with national healthcare data from the Health Insurance Review and Assessment Service. The analytical variables included changes in workforce composition, initial treatment modalities, HCC stage distribution, quality indicators for HCC care, regional and institutional variations in care delivery, and liver transplantation (LT) volume. A comparison between 2023 and 2024 revealed a marked decline in the number of medical trainees, a rise in the proportion of physician assistants, a 28.9% reduction in newly initiated HCC treatments, and an increased rate of stage IV diagnoses. Several quality indicators, including rates of multidisciplinary care and patient education, declined. The volume of LTs decreased by approximately 20% nationwide, with some regions ceasing LT procedures. The results suggest that serious disruptions occurred in HCC care following the conflict. The significant decrease in initial treatment and number of LT procedures, more advanced stages at diagnosis, and declining quality metrics indicate the emergence of healthcare gaps. Without the recovery of the clinical workforce and the reestablishment of a stable healthcare delivery system, the management of serious diseases such as HCC will remain structurally vulnerable. National-level efforts are urgently required to address regional disparities and restore essential medical services.

Original Article

Association between metabolites and hepatocellular carcinoma: findings from a two-sample Mendelian randomization study: Tung Hoang, Van Mai Truong, Tho Thi Anh Tran, Bao Le Thai Tran, Ngoc Hong Cao; J Liver Cancer. 2025;25(2):251-265. Published online September 2, 2025; DOI: https://doi.org/10.17998/jlc.2025.08.26

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63 Downloads
1 Web of Science
1 Citation

Abstract PDF Supplementary Material

Backgrounds/Aims
Identifying metabolic biomarkers can enhance early detection and risk stratification of hepatocellular carcinoma (HCC). We conducted a two-sample Mendelian randomization (MR) study to assess the potential causal effects of metabolites on HCC risk.
Methods
We performed meta-analyses to pool the effects of genetic instruments from 64 previously published genome-wide association studies. Summary statistics for HCC were obtained from a meta-analysis of the UK BioBank and FinnGen cohorts. MR analyses for the association between 3,275 metabolites and HCC risk were performed using inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO methods to estimate the association. Enrichment analyses were performed on the significant metabolites to identify biological pathways associated with macronutrient intake.
Results
We identified 99 metabolites that were positively and 36 metabolites that were negatively associated with HCC risk. Methyl glucopyranoside and phosphatidylcholine C38:3 were positively associated with HCC risk, whereas while 3-dehydrocarnitine and 10-undecenoate were inversely associated, with no evidence of heterogeneity, pleiotropy, or outlier effects for any of these associations. Pathway enrichment analysis showed that metabolites associated with increased HCC risk were primarily related to amino acid transport and solute carrier transporter disorders, whereas those linked to reduced risk were mainly involved in inositol and phosphatidylinositol metabolism, glycerophospholipid catabolism, and MeCP2-related regulatory processes.
Conclusions
This comprehensive MR study identified several metabolites with potential causal roles in HCC development. Our findings highlight nutrient transport, lipid metabolism, and related regulatory mechanisms as key components of HCC pathogenesis, offering new avenues for biomarker discovery and therapeutic intervention.

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Multi-omics integration identifies cell-type-specific CISD1 and QDPR as druggable regulators linking hepatocellular carcinoma and major depressive disorder
Longyang Sun, Junjie Bi, Jianguang Sun
Psychiatry Research.2026; 364: 117277. CrossRef

Review Articles

Navigating liver cancer with mouse models: a comprehensive overview of HCC experimental systems: Ga-Young Kim, Dokyung Kim, Jaehyun Jeon, Wonhyo Seo, Seol Hee Park; J Liver Cancer. 2025;25(2):239-250. Published online August 22, 2025; DOI: https://doi.org/10.17998/jlc.2025.08.21

10,193 Views
255 Downloads
4 Web of Science
4 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is the most prevalent primary hepatic malignancy and is globally the third leading cause of cancerrelated deaths. Despite significant advancements in diagnostic techniques and therapeutic interventions, HCC prognosis remains poor due to asymptomatic progression, frequent recurrence, and inadequate treatment responsiveness. The development of HCC is closely linked to chronic liver diseases, such as hepatitis B and C infections, alcoholic liver disease, and metabolic dysfunctionassociated steatotic liver disease (MASLD). To better understand hepatocarcinogenesis and support therapeutic development, a range of animal models have been established. Among these animal models, mice are extensively utilized because of their genetic manipulability, physiological resemblance to humans, and relatively short experimental timelines. The most well-established protocol for analyzing the onset and progression of HCC is the diethylnitrosamine (DEN)-induced HCC model. Additionally, carbon tetrachloride (CCl₄)-induced HCC models, DEN+CCl₄ combination HCC models, MASLD HCC mouse models (STAM^TM), alcoholassociated HCC models, hydrodynamics-based transfection systems, and orthotopic HCC transplantation approaches also provide distinct advantages for exploring specific elements of HCC pathophysiology. Unfortunately, due to the complexity and heterogeneity of human HCC, no single animal model can accurately recapitulate the disease. Therefore, careful selection or combination of appropriate mouse models for specific research objectives is crucial to enhance the translational value of preclinical studies. This review provides a comprehensive overview of the mouse models currently employed in HCC research, highlighting their respective strengths and limitations. Such understanding and application of these HCC models are essential for advancing mechanistic insights and fostering the development of novel therapeutic strategies.

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Single-Cell Transcriptomic Profiling Reveals That Macrophage-Induced Angiogenesis Contributes to Immunotherapy Resistance in Hepatocellular Carcinoma
Xinyu Pan, Baolin Liao, Zhijie Hu, Yuanyan Xiong
Biology.2026; 15(1): 95. CrossRef
Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation
Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A. Villeda, Hao Li
Proceedings of the National Academy of Sciences.2026;[Epub] CrossRef
Single-cell and bulk RNA-seq with machine learning reveals CCNB1/CDK1-mediated G2/M arrest as key anti-HCC mechanism of Fuzheng Xiaozheng Prescription
Xia Li, Bowen Zhu, Jiexiong Yang, Min Hu, Xiangsen Lan, Xinwen Zhang, Yuxi Cao, Ziwei Tang, Wenjun Wu, Cen Jiang, Quansheng Feng
Phytomedicine.2026; 160: 158683. CrossRef
Risk of HCC in Elderly Patients With MASLD: Proposal of an Effective Surveillance Strategy
Young Eun Chon, Kyung‐Do Han, Ju Dong Yang, Ju‐Yeong Park, Hyun‐Seok Kim, Hyung Woong Lee, Tae Seop Lim, Beom Kyung Kim
Journal of Gastroenterology and Hepatology.2026;[Epub] CrossRef

Preventing false positive imaging diagnosis of HCC: differentiating HCC from mimickers and practical strategies: Ijin Joo; J Liver Cancer. 2025;25(2):217-232. Published online July 31, 2025; DOI: https://doi.org/10.17998/jlc.2025.07.29

9,751 Views
138 Downloads
4 Web of Science
7 Citations

Abstract PDF

Noninvasive imaging-based diagnosis of hepatocellular carcinoma (HCC) in high-risk patients plays a central role in clinical practice. Current major guidelines typically rely on the radiologic hallmark of nonrim arterial phase hyperenhancement followed by nonperipheral washout, criteria designed to achieve both high positive predictive value and sufficient specificity when applied within well-defined target populations. Despite these criteria, false positive diagnoses still occur and can lead to unnecessary or inappropriate treatment, as various benign and non-HCC malignant lesions may exhibit vascular features that overlap with the classic appearance of HCC. Furthermore, treatment decisions are occasionally guided by imaging findings even in patients outside the target population who are being evaluated for possible HCC, in whom vascular patterns are less specific and the risk of false positive diagnosis is inherently higher. Minimizing the risk of false positive diagnosis requires not only adherence to validated imaging criteria but also clinical and contextual integration when findings are uncertain. This includes consideration of ancillary features, tumor markers, and, when appropriate, further evaluation through biopsy, additional imaging, or follow-up. This review outlines a range of HCC mimickers and provides practical strategies to support accurate imaging interpretation and reduce false positive diagnoses in clinical practice.

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Imaging differentiation of hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma: pitfalls and advances
Jaeseung Shin, Taek Chung, Sang Yun Ha, Hyungjin Rhee
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Journal of Hepatology.2026;[Epub] CrossRef

Special Contribution

Expert survey on systemic therapy indications for hepatocellular carcinoma in Korea: bridging clinical practice and reimbursement criteria: Hyun Yang, Soon Sun Kim, Seong Hee Kang, Jieun Kwon, Do Young Kim, Eunju Kim, Hyun Phil Shin, Jeong Il Yu, Jeong-Ju Yoo, Eileen L. Yoon, Sangheun Lee, Young Eun Chon, Janghan Jung, Jaekyung Cheon, Woosun Choi, Seul Ki Han, Ji Eun Han, Moon Haeng Hur, Hyun Woong Lee, Hyung Joon Kim; J Liver Cancer. 2025;25(2):160-168. Published online July 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.07.02

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Abstract PDF: This survey aimed to collect expert opinions from multidisciplinary specialists involved in the management of hepatocellular carcinoma (HCC) in Korea regarding real-world criteria for systemic therapy indications. In response to discrepancies between national reimbursement policies and clinical decision-making, members of the Korean Liver Cancer Association and Korean Association for the Study of the Liver participated in a web-based survey from February 4 to 14, 2025. A total of 89 respondents, primarily experienced clinicians, provided their views on major clinical scenarios including infiltrative HCC, bilobar multifocal disease, huge tumors, vascular invasion, extrahepatic metastasis, and transarterial chemoembolization (TACE) refractoriness. There was high agreement for including infiltrative HCC (69.7%), suspected portal vein invasion (70.8%), and TACE refractoriness (82.0%) as systemic therapy indications. TACE refractoriness, in particular, aligns with current guideline definitions. Additionally, over half of respondents (51.7%) supported extrahepatic metastasis under similar conditions. Notably, multidisciplinary discussion was emphasized across scenarios, but many respondents also favored allowing primary physician discretion in select cases. This report provides consolidated expert input to inform future updates to reimbursement policies and promote alignment with real-world clinical practice. These findings may help bridge the gap between national coverage criteria and clinical decision in systemic therapy for HCC.

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