BackgroundTraditional Chinese medicine (TCM) demonstrates growing potential in liver cancer management, yet a comprehensive overview mapping the intellectual landscape and evolving trends of this field is lacking. This study aims to fill this gap by conducting a systematic bibliometric analysis of TCM for liver cancer research over the past decade.MethodsWe performed a bibliometric analysis of publications related to TCM and liver cancer retrieved from major databases including China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and Web of Science. The search timeframe spanned from February 14, 2015, to the search date (February 14, 2025). The literature was analyzed using scientific mapping tools, such as CiteSpace, Origin 2024, R, and VOSviewer, to identify publication trends, collaborative networks, research hotspots, and frontier topics.ResultsThe analysis reveals a steadily growing and globally engaged field, with China being the dominant contributor. While core research teams are emerging, international and cross-regional collaborations remain limited. A clear thematic divergence exists: international literature primarily focuses on exploring the pharmacological mechanisms of TCM compounds, whereas Chinese-language studies place greater emphasis on clinical applications, medication rules, data mining, and TCM syndrome differentiation. Key emerging research frontiers include mechanisms of action, omics technologies, bioinformatics technology, network pharmacology and molecular docking, TCM syndrome research, TCM theory innovation and exploration, TCM nanodelivery, data mining, and deep learning.ConclusionThis bibliometric review provides a comprehensive landscape of TCM research for liver cancer, highlighting its dynamic growth and the complementary nature of mechanistic and clinical research streams. The findings underscore the necessity for enhanced international collaboration to bridge existing gaps and foster integrated, innovative approaches for advancing TCM in oncology.

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the high prevalence of drug resistance. The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), a core component of the Polycomb Repressive Complex 2, is frequently overexpressed in HCC and drives of drug resistance. This review delineates the multifaceted mechanisms by which EZH2 promotes resistance to chemotherapy, targeted therapy, and immunotherapy. We detail how EZH2 orchestrates pro-survival pathways by modulating cell cycle checkpoints, inhibiting apoptosis, enhancing DNA repair, and fostering an immunosuppressive tumor microenvironment. Furthermore, we evaluate the current landscape of EZH2 inhibitors, from clinically approved agents to novel therapeutic modalities like PROTACs, and discuss their potential to re-sensitize HCC to treatment. Finally, we outline future research directions, emphasizing combination strategies and biomarker development, to advance EZH2-targeting therapies for HCC.

BackgroundSurgical resection and ablation therapy are both primary treatment options for very early stage hepatocellular carcinoma (HCC). Accurate risk stratification is important, since patients at higher risk of recurrence may derive greater benefit from curative resection than from ablation. We investigated whether the mitotic index is associated with early recurrence in HCC and may serve as a prognostic marker to refine risk assessment in very early stage disease.MethodsThe number of mitoses was counted in representative tumor slides from 942 cases of surgically resected HCC from Samsung Medical Center. A high mitotic index was defined as more than eight mitoses in 10 high-power fields. The relationship between mitotic index, clinicopathological characteristics, and prognosis were analyzed. External validation was performed using 112 HCC cases obtained from Hallym University Sacred Heart Hospital.ResultsHigh mitotic index was identified in 296 patients and was significantly associated with aggressive clinicopathological features including higher Edmondson grade, advanced American Joint Committee on Cancer T stage, and early tumor recurrence. Patients with a high mitotic index displayed a significantly shorter early recurrence-free survival (e-RFS). In subgroup analysis of patients with very early stage, the high mitotic index group showed unfavorable influences on e-RFS.ConclusionHigh mitotic index is a significant predictor of early recurrence in HCC patients and may provide useful prognostic information in very early stage disease. While its direct role in guiding primary treatment selection is limited, the mitotic index could contribute to risk stratification and postoperative management strategies.

AimThe prognosis of hepatocellular carcinoma with extrahepatic spread (HCC-EHS) remains poor. While systemic therapy is standard, intrahepatic progression often drives mortality. This study evaluated whether combining transarterial chemoembolization (TACE) with sorafenib (TACES) improves outcomes versus TACE alone in HCC-EHS.MethodsIn this multicenter, retrospective study, 423 HCC-EHS patients (Child-Pugh A) were categorized into TACE-alone (n = 294) or TACES (n = 129) groups. The primary endpoint was overall survival (OS). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. Radiological response was assessed per mRECIST.ResultsAfter IPTW adjustment, the TACES group demonstrated significantly superior tumor response, with higher objective response (33.3% vs 16.4%, p = 0.004) and disease control rates (63.2% vs 46.3%, p = 0.008) compared to the TACE-alone group. This translated into a significant survival benefit, with a median OS of 10.4 months for TACES versus 7.0 months for TACE alone (IPTW-adjusted hazard ratio: 0.68; 95% CI: 0.52–0.88; p = 0.004). The survival advantage remained consistent in landmark analyses. Subgroup analyses indicated that the absolute benefit from combination therapy was most pronounced in patients with high intrahepatic tumor burden and preserved liver function.ConclusionThis real-world study demonstrates that in carefully selected patients with HCC-EHS, a combination of TACE and sorafenib provides significantly better tumor control and survival outcomes than TACE monotherapy. These findings suggest that an integrated therapeutic strategy, which aggressively manages the intrahepatic disease in conjunction with systemic therapy, can improve outcomes in this challenging-to-treat population and warrants validation in prospective studies.

PurposeLiver cancer, predominantly hepatocellular carcinoma (HCC), represents a significant health burden in Saudi Arabia, ranking as the 8th most common cancer in males and 14th in females. Accurate prevalence estimation is essential for healthcare planning, resource allocation, and understanding disease burden. Challenges in prevalence assessment include incomplete capture of historical cases by the Saudi Cancer Registry (SCR) before its full operational capacity, as well as the absence of dedicated prevalence surveys. This study estimates the point prevalence of HCC in Saudi Arabia for the year 2021 using population-based incidence data, survival estimates, and census information.Patients and MethodsA population-based prevalence estimation study was conducted using incident HCC cases reported to the SCR (2005–2017), population census data (2005–2020), and published national survival data. The study population comprised all newly diagnosed HCC cases reported during the study period. Prevalence was calculated by multiplying incident cases from each diagnosis cohort by their corresponding age- and gender-specific survival probabilities to estimate the number of HCC survivors alive in 2021, divided by the population at risk. Monte Carlo simulation with binomial distribution (n = incident cases; p = survival probability) was performed 1000 times to generate a distribution of prevalent cases, with 2.5th and 97.5th percentiles defining 95% confidence intervals. Age- and gender-specific prevalence rates were standardized to the WHO 2000–2025 World Standard Population using direct standardization for international comparability.ResultsBetween 2005 and 2020, 6743 HCC cases were newly diagnosed and reported to the SCR, comprising 4685 males (69.5%) and 2058 females (30.5%). By the end of 2020, the estimated number of male HCC survivors was 637.3 (95% CI: 612.8–663.2), while females numbered 496.9 (95% CI: 474.1–521.8). In 2021, the age-standardized prevalence rate of HCC was 8.62 per 100,000 population for males (95% CI: 8.28–8.98) and 6.36 per 100,000 for females (95% CI: 6.08–6.67), with an overall combined age-standardized rate of 7.49 per 100,000 (95% CI: 7.25–7.76). HCC prevalence increased progressively with age, with the highest proportion of diagnosed cases occurring in individuals aged 75 years and above (males: n=1315; females: n=420). Younger cohorts diagnosed after 2015 showed markedly improved survival rates compared to those diagnosed in 2005, reflecting advances in treatment modalities.ConclusionThis study provides a comprehensive population-based estimate of HCC prevalence in Saudi Arabia, demonstrating substantial gender and age disparities in disease burden. The predominance of HCC in males and elderly populations underscores the need for targeted epidemiological research to identify modifiable risk factors, particularly given the markedly lower prevalence of alcohol-related liver disease compared to global HCC endemic regions. The methodological framework utilizing integration of incidence, population-based survival data, and WHO standardization provides a replicable model for disease burden estimation in countries with limited prevalence survey infrastructure. Future research should focus on disease etiology, including the role of chronic hepatitis B, chronic hepatitis C, metabolic-associated steatotic liver disease, and the evolving patterns of liver disease in Saudi Arabia.

BackgroundTumor-associated macrophages (TAMs) are pivotal components of the immune cell infiltrate in tumors and cell division cycle-associated protein-3 (CDCA3) is associated with tumor progression. The role of CDCA3 in regulating TAM polarization remains uncharacterized in hepatocellular carcinoma (HCC).MethodsCDCA3 expression, its correlation with immune cell infiltration, and prognostic significance in HCC were analyzed using the TCGA and TIMER databases. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), were performed to predict CDCA3-related pathways. The knockdown efficiency of CDCA3 in HCC cell lines was confirmed by RT-qPCR and Western blotting. Functional assays, including CCK-8, wound healing, and flow cytometry, were used to assess the role of CDCA3 in cell proliferation, migration, and apoptosis. Immunohistochemistry (IHC) was applied to evaluate the correlation between CDCA3 expression and M2 macrophage markers in clinical tissue samples.ResultsBioinformatic analysis revealed that CDCA3 was significantly upregulated in HCC tissues, and its high expression was associated with advanced clinical stage, higher tumor grade, and poor prognosis. CDCA3 expression also correlated strongly with the level of immune infiltration. Notably, CDCA3 showed high diagnostic potential for HCC, with an area under the curve (AUC) of 0.869, cut-off value of 189.03 pg/mL, sensitivity of 81.9%, and specificity of 77.8%. Experimentally, CDCA3 knockdown significantly suppressed malignant phenotypes of HCC cells and inhibited M2 macrophage polarization.ConclusionOur findings suggest that CDCA3 promotes the malignant progression of HCC by driving M2-like TAM polarization, potentially through the upregulation of cytokines such as TGF-β1, VEGFA, CD40, CXCL1, and CXCL5. CDCA3 thus represents a promising diagnostic biomarker and therapeutic target for HCC.

PurposeCircadian disruption contributes to hepatocellular carcinoma (HCC) progression. This study aimed to develop a CT-based radiomics model to non-invasively predict circadian rhythm (CR) gene expression profiles for improved prognostic assessment.MethodsMendelian randomization (MR) analysis revealed a significant causal association between CR disorders and the risk of HCC. In Cohort 1 (TCGA database, n = 424), 32 CR-related genes were identified from an initial set of 71 genes. Univariate Cox regression analysis identified 18 prognosis-related genes, and a risk model containing 8 genes was constructed using LASSO and multivariate Cox regression. This model was then validated in Cohort 2 (ICGC database, n = 232). The gene CRTC2 was further validated in vitro. Radiomics features were constructed based on enhanced CT images from Cohort 3 (TCIA database, n = 45) to predict CR risk genes, and the prognostic value of the model was validated in Cohort 4 (The Fourth Affiliated Hospital of Zhejiang University School of Medicine, n = 38).ResultsThe CR risk gene model stratified patients into high- and low-risk groups with significantly different survival outcomes in both TCGA and ICGC cohorts (TCGA: P < 0.001; ICGC: P = 0.029). The risk score was independently associated with overall survival (HR = 3.582, 95% CI: 2.101–6.107, P < 0.001). Experimental results confirmed that knockdown of CRTC2 significantly inhibited HCC cell proliferation, migration, invasion, and induced apoptosis. The radiomics model achieved an AUC of 0.931 in the training set and 0.760 in the validation set for predicting CR gene expression. Importantly, in the clinical validation cohort, patients with low radiomics scores had significantly longer survival (P = 0.039).ConclusionCircadian rhythm-related gene expression, implicated in HCC development, can be non-invasively predicted via CT-based radiomics. The proposed model offers promise for prognostic stratification and personalized treatment planning in HCC.

PurposeTertiary lymphoid structure (TLS) has been well-established across multiple tumor types for predicting efficacy of immunotherapy and prognostic evaluation. However, its role in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unclear. Refinement of TLS pathological assessment could potentially optimize postoperative management in these patients. This study aimed to develop a practical histopathological grading system of intratumoral TLS to improve prognostic stratification of cHCC-CCA patients.Patients and MethodsA cohort of 310 cHCC-CCA patients undergoing hepatectomy with curative intent was analyzed. Three pathologists re-evaluated pathological slides to establish a four-tier TLS grading system: TLS 0 (absent), TLS 1 (immature TLS only), TLS 2a [single mature TLS (mTLS)], and TLS 2b (multiple mTLS). Associations with recurrence-free survival (RFS), overall survival (OS), early RFS (≤1 year), late RFS (>1 year), and recurrence patterns were assessed. Predictive factors for TLS were also investigated.ResultsPatients were stratified into TLS 0 (29.4%), TLS 1 (51.6%), TLS 2a (6.8%), and TLS 2b (12.3%). Survival outcomes significantly correlated with TLS presence and maturation. Median RFS increased stepwise: 0.24 years (TLS 0), 0.49 years (TLS 1), 1.13 years (TLS 2a), and 1.16 years (TLS 2b) (P<0.001). Median OS also improved progressively: 1.32 years (TLS 0), 2.20 years (TLS 1), 3.24 years (TLS 2a), and 10.04 years (TLS 2b) (P<0.001). TLS presence was associated with increased extrahepatic recurrence. The TLS grading system emerged as an independent prognostic factor for RFS, OS, and early RFS. Smaller tumor diameter was the sole significant predictive factor for both TLS and mTLS.ConclusionThis novel TLS grading system effectively stratifies prognosis in cHCC-CCA, with increasing intratumoral mTLS indicating better outcomes. This practical method can be integrated into routine pathological reporting to aid clinical decision-making.

BackgroundThe influence of pyroptosis on tumors is complex and diverse. However, its specific impact on hepatocellular carcinoma (HCC) is still not well understood. Therefore, the objective of this study was to develop a prognostic signature for HCC based on pyroptosis-related genes.MethodsThe single-cell RNA sequencing (scRNA-seq) data, mRNA expression files and corresponding clinical information of HCC were obtained from the The Cancer Genome Atlas and Gene Expression Omnibus databases. Python was used to process scRNA-seq data and calculated the enrichment score of pyroptosis-related genes (PRGs). Weight Co-Expression Network Analysis was used to identify pyroptosis-related hub genes. By overlapping the PRGs from scRNA-seq analysis and bulk RNA-seq analysis, respectively. Then, Univariate cox and LASSO regression were used to construct the pyroptosis prognostic model. Multivariate cox was used to identify independent factors for HCC and then developed a nomogram. The biological functions, survival analysis, immune characteristics, therapy response, and m6A modification status were analyzed.ResultsBased on the scRNA-seq analysis and bulk RNA-seq analysis, hub PRGs were identified in HCC. Of those genes, five PRGs (ADGRE2, FCER1G, SLC9A9, CYBB, SLAMF6) were selected as a prognostic signature. The risk score established from the prognostic signature was an independent prognostic factor for HCC. The high-risk score group is associated with a poor prognosis, characterized by immunosuppressive features.ConclusionThis study uniquely integrates single-cell and bulk transcriptomic data to systematically identify pyroptosis-related prognostic biomarkers, pinpointing their cellular origin within the tumor microenvironment.