Although bacteria have been detected in hepatocellular carcinoma (HCC), the low microbial biomass has hindered isolation of viable intratumoral strains and evaluation of their functional relevance. Intratumoral micro-biota profiling by 5R 16S rRNA sequencing, together with a stringent contamination-controlled workflow, identified enrichment of Staphylococcus in advanced-stage (Barcelona Clinic Liver Cancer [BCLC] C) HCC and enabled isolation of a viable S. epidermidis strain, GX3-2, from HCC tissue. GX3-2 promoted HCC cell proliferation and migration in vitro and was associated with accelerated xenograft growth in a pilot intratumoral inoculation model. Multi-omics analyses linked GX3-2 to distinct metabolic features, including adenosine and 2-phenylethyla mine (2-PEA), together with host transcriptional programs related to cell cycle and epithelial-mesenchymal transition. These findings provide proof-of-concept evidence that a tumor-derived S. epidermidis isolate may modulate malignant phenotypes in HCC.

Gallbladder cancer (GBC) is a lethal malignancy with limited therapeutic options and dismal prognosis. Identifying the factors driving GBC progression is crucial for developing potent preventive and therapeutic approaches. Here, using quantitative proteomics, we identify GALNT7 as the most significantly upregulated glycosyltransferase in GBC tissues, associated with adverse clinical outcomes. Mechanistically, GALNT7 physically interacts with TAZ and catalyzes O-GalNAcylation at Ser307, thereby inhibiting K48-linked ubiquitination through the recruitment of the deubiquitinase USP7 and stabilizing the TAZ protein. This post-translational modification promotes TAZ accumulation and subsequent activation of TEAD1-mediated transcription, which in turn upregulates GALNT7 expression, thereby establishing a self-reinforcing oncogenic feedback loop. Disruption of TAZ O-GalNAcylation via the S307A mutation abrogates its oncogenic activity and attenuates GALNT7-driven tumor progression. Importantly, structure-based drug-repurposing screens identified the PARP inhibitor Olaparib as a direct GALNT7 antagonist that effectively inhibits TAZ O-GalNAcylation and demonstrates potent anti-tumor efficacy against GBC both in vitro and in vivo. Collectively, our findings reveal a glycosylation-dependent regulatory axis that drives GBC progression and establish GALNT7-TAZ signaling as a tractable therapeutic target.

This study used a two-sample Mendelian randomization (MR) method to explore the potential causal relationship between air quality, cholelithiasis, and its related risk factor, blood lipids. This study used MR in European and East Asian groups, utilizing publicly available genome-wide association study data. The main method was inverse-variance weighting, with additional quality checks including weighted median, MR-Egger, simple, and weighted models. The Cochran Q test assessed heterogeneity. MR-Egger regression and MR-PRESSO checked for gene pleiotropy, with sensitivity tests using leave-one-out analysis. No statistically significant association was observed between air pollution and cholelithiasis in both European and East Asian populations for all pollutants analyzed, including PM2.5 (European: P = .745, East Asian: P = .209), PM2.5 to 10 (European: P = .737), PM10 (European: P = .258, East Asian: P = .977), nitrogen dioxide (European: P = .986, East Asian: P = .893), and nitrogen oxides (European: P = .902, East Asian: P = .843). However, significant correlations between air pollution and blood lipids were identified. In European populations, PM2.5 was significantly correlated with triglycerides (β = 0.428, odds ratio = 1.534, 95% confidence interval = 1.058-2.225; P = .024). In East Asian populations, PM2.5 showed a significant association with low-density lipoprotein (LDL) cholesterol (β = 0.050, odds ratio = 1.051, 95% confidence interval = 1.006-1.098; P = .026). Importantly, no evidence of heterogeneity or pleiotropy was detected in these associations, bolstering the credibility of our findings. Our study found no clear causal link between air pollution and cholelithiasis. However, we observed significant correlations between PM2.5 and triglycerides in Europeans, and between PM2.5 and LDL cholesterol in East Asians. These results suggest that PM2.5 might affect triglyceride and LDL cholesterol metabolism differently in various populations, potentially raising the risk of cholelithiasis indirectly.

Background and aim:Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with limited prognostic tools to guide treatment strategies. This study aimed to develop and validate a preoperative prognostic model combining tumor burden score (TBS), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9), termed the TCCA model, to predict outcomes in patients with ICC undergoing hepatectomy. Methods:Patients who underwent curative resection for ICC between 2014 and 2020 were retrospectively identified from a multi-institutional database. The impact of the TCCA model on overall survival (OS) and recurrence-free survival (RFS) was evaluated in training and validation cohorts. Predictive performance was evaluated using the area under the Receiver Operating Characteristic curve (AUC), the Akaike Information Criterion (AIC), and the C-index. Results:A total of 849 patients were included. Lower TCCA scores were associated with better median OS (score 0: 59.7 months; score 1: 31.3 months; score 2: 19.4 months; score 3: 11.5 months, respectively) and median RFS (28.8; 15.4; 9.7; 8.1 months, respectively). The TCCA model performed well in both the training cohort (AUC: 0.697 for OS and 0.649 for RFS) and the validation cohort (AUC: 0.672 for OS and 0.632 for RFS), outperforming the 8th edition TNM system and other models, with the highest C-index (0.734) and lowest AIC (3840). Subgroup analyses demonstrated that the TCCA model maintained good discriminative ability among patients with negative CEA or CA19-9 levels. Conclusion:The TCCA model accurately stratifies ICC patients for OS and RFS after resection. It provides a simple and practical tool for preoperative risk assessment, supporting individualized surgical decision-making and individualized patient counseling.

Background Neddylation is a critical post-translational modification that is frequently hyperactivated in various human cancers. By modifying key substrates such as Cullins and non-Cullin proteins, this pathway plas a central role in regulating protein stability, cellular signaling transduction, and core biological processes. Its dysregulation directly drives tumorigenesis and progression, making it a highly promising therapeutic target. Aim of review This review aims to systematically elucidate: (1) the processes of neddylation and its regulatory mechanisms on cellular and protein functions; (2) how this pathway promotes malignant progression and tumorigenesis by driving multiple cancer hallmarks; and (3) the development of drugs targeting different neddylation components, along with associated clinical trial progress and toxicity challenges, while also discussing its future prospects in precision oncology. Key scientific concepts of review This review constructs a multi-dimensional pathogenic network of neddylation at a systematic level, providing a comprehensive elaboration of its molecular basis in governing key cancer characteristics through modulating protein functions and cellular activities. Simultaneously, we focus on targeted therapeutic strategies against this pathway, analyzing the clinical potential and future directions of novel cancer treatment approaches based on preclinical and clinical evidence from inhibitors such as MLN4924 and TAS4464.

This study aimed to examine postoperative prognostic factors in patients with T2 gallbladder cancer (GBC) to determine factors linked to survival outcomes. The results can inform clinical decision-making and guide personalized treatment plans. The Cochrane Library, PubMed, Web of Science, and Embase databases were retrieved up to March 12, 2025. The included articles were scored via the Newcastle-Ottawa Scale (NOS). The data were analyzed via Stata 15.0. Twenty-one studies (n = 8,095) were included. Factors associated with worse overall survival (OS) included age > 60 years (hazard ratio [HR] = 1.02, 95

BACKGROUND AND AIM:The prognostic significance of liver resection for multifocal intrahepatic cholangiocarcinoma (ICC) remains controversial and is further complicated by the lack of reliable predictive models. This study aims to develop a prognostic Classification and Regression Tree (CART) model for resectable multifocal ICC. METHODS:This retrospective, multicenter cohort study included 283 patients who underwent liver resection for multifocal ICC between 2008 and 2020. Prognostic variables identified via multivariable Cox regression were used to construct a CART model. The predictive accuracy of the CART model was internally validated through 5-fold cross-validation and compared to Wang and Hyder nomogram. RESULTS:Bilobar tumors, largest tumor size >6 cm, tumor number >2, and Carbohydrate Antigen 19-9 >37 U/mL were associated with poorer survival. The CART model stratified patients into three risk groups. Patients with two unilobar tumors and largest tumor size ≤6 cm had the most favorable prognosis, with a median OS of 37.5 months and 5-year OS of 25.6 %. In contrast, those with bilobar involvement and CA19-9 >37 U/mL had the poorest outcomes, with a median OS of 11.2 months and 5-year OS of 0 %, regardless of tumor size or number. The area under the receiver operating characteristic curve (AUC) of the CART model in internal validation was 0.728. The time-dependent AUC for the CART model was 0.711, exceeding that of the Wang (0.644) and Hyder (0.618) nomograms. CONCLUSION:The CART model provides accurate and interpretable survival prediction for patients with resectable multifocal ICC and may assist in preoperative surgical decision-making.

Background Bone metastasis considerably undermines the prognosis of advanced primary liver cancer patients. Though its impact is well-recognized, the clinical field still lacks robust predictive models that can accurately forecast patient outcomes and aid in treatment effectiveness evaluation. Addressing this gap is paramount for improving patient management and survival. Materials and methods We conducted an extensive analysis using data from the SEER database (2010-2020). COX regression analysis was applied to identify prognostic factors for primary liver cancer with bone metastasis (PLCBM). Nomograms were developed and validated to predict survival outcomes in PLCBM patients. Additionally, propensity score matching and Kaplan-Meier survival analyses lent additional insight by dissecting the survival advantage conferred by various treatment strategies. Results A total of 470 patients with PLCBM were included in our study. The median overall survival (OS) and cancer-specific survival (CSS) for these patients were both 5 months. We unveiled several independent prognosticators for OS and CSS, spanning demographic to therapeutic parameters like marital status, cancer grade, histological type, and treatments received. This discovery enabled the formulation of two novel nomograms—now verified to eclipse the predictive prowess of the traditional TNM staging system regarding discrimination and clinical utility. Additionally, propensity score matching analysis showed the effectiveness of surgeries, radiotherapy, and chemotherapy in improving OS and CSS outcomes for PLCBM patients. Conclusions Our investigation stands out by introducing pioneering nomograms for prognostic evaluation in PLCBM, a leap forward compared to existing tools. Far exceeding mere academic exercise, these nomograms hold immense clinical value, serving as a foundation for nuanced risk stratification systems and delivering dynamic, interactive guides, allowing healthcare professionals and patients to assess individual bone metastasis survival probabilities and personalize treatment selection.

Background The prognostic significance of tumor burden score (TBS) in relation to carcinoembryonic antigen (CEA) has not been investigated among patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). This study aimed to develop and validate a simplified model, a combination of TBS and CEA (CTC grade), for predicting the long-term outcomes of postoperative ICC patients. Methods Patients who underwent curative − intent resection of ICC between 2011 and 2019 were identified from a large multi − institutional database. The impact of TBS, CEA, and the CTC grade on overall survival (OS) and recurrence − free survival (RFS) was evaluated in both the derivation and validation cohorts. The receiver operating characteristic curve was utilized for assessing the predictive accuracy of the model. Subgroup analyses were performed across 8th TNM stage system stratified by CTC grade to assess the discriminatory capacity within the same TNM stage. Results A total of 812 patients were included in the derivation cohort and 266 patients in the validation cohort. Survival varied based on CEA (low: 36.7% vs. high: 9.0%) and TBS (low: 40.3% vs. high: 17.6%) in relation to 5 − year survival (both p < 0.001). As expected, patients with low CTC grade (i.e., low TBS/low CEA) were associated with the best OS as well as RFS, while high CTC grade (i.e., high TBS/high CEA) correlated to the worst outcomes. The model exhibited well performance in both the derivation cohort (area under the curve of 0.694) and the validation cohort (0.664). The predictive efficacy of the CTC grade system remains consistently stable across TNM stages I and III/IV. Conclusion The CTC grade, a composite parameter derived from the combination of TBS and CEA levels, served as an easy − to − use tool and performed well in stratifying patients with ICC relative to OS and RFS.

As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).

Abstract Background Radical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients. Methods Data of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared. Results Two hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child–Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05. Conclusion Surgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

Abstract Objective Hepatocellular carcinoma (HCC) is an extremely deadly cancer with few effective therapeutic options available. Ceramide synthases (CERS), a family of enzymes that regulate sphingolipid metabolism, have been suggested to play a role in cancer initiation and progression. Whereas the specific functions of CERS in HCC pathogenesis have not yet been fully elucidated. Methods The TCGA and ICGC databases were employed to analyze the expression levels and clinical relevance of CERS genes in HCC. Functional enrichment analyses were performed to identify pathways and functions associated with CERS5. The correlation between CERS5 and the tumor immune microenvironment was investigated. The mutation landscape and immunotherapy efficacy were evaluated. Functional experiments in vitro were conducted to assess CERS5’s impact on HCC cell proliferation and invasion. Results Aberrant expression of the CERS family was detected not only in HCC but also in other cancers, and has been linked to both overall survival and disease-free survival. Among the CERS family members, CERS5 was identified as the only prognosis-related gene, with up-regulated in HCC validated in the ICGC database and clinical tissue samples. Higher expression levels of CERS5 were associated with a poorer prognosis as well as an advanced pathologic stage and grade, as confirmed by the TCGA and ICGC databases. Besides, a prognostic nomogram combining pathologic stage, tumor status, and the expression of CERS5 was established and further validated, which suggested a favorable value for prognosis prediction. Functional enrichment analyses showed that the overexpression of CERS5 resulted in enriched pathways associated with carcinogenesis, drug metabolism, the PI3K/AKT/mTOR signaling pathway, and cancer immune-related pathways. In addition, the overexpression of CERS5 correlated positively with the expression of genes associated with immunogenic cell death modulators and immune checkpoints, levels of immune cell infiltration, and immunotherapy response, which was featured in an immunologically “hot” environment in the tumor microenvironment. Finally, the functional experiments showed that CERS5 knockdown has been shown to inhibit the growth and invasion of hepatocellular carcinoma, potentially through targeting the PI3K/AKT/mTOR signaling pathway. Conclusions Based on our findings, CERS5 appears to have great potential as both a precise prognostic biomarker and a novel therapeutic target in HCC.

BackgroundDespite advancements in hepatocellular carcinoma (HCC) treatments, the prognosis for patients remains suboptimal. Cumulative evidence suggests that programmed cell death (PCD) exerts crucial functions in HCC. PCD-related genes are potential predictors for prognosis and therapeutic responses.MethodsA systematic analysis of 14 PCD modes was conducted to determine the correlation between PCD and HCC. A novel machine learning-based integrative framework was utilized to construct the PCD Index (PCDI) for prognosis and therapeutic response prediction. A comprehensive analysis of PCDI genes was performed, leveraging data including single-cell sequencing and proteomics. GBA was selected, and its functions were investigated in HCC cell lines by in vitro experiments.ResultsTwo PCD clusters with different clinical and biological characteristics were identified in HCC. With the computational framework, the PCDI was constructed, demonstrating superior prognostic predictive efficacy and surpassing previously published prognostic models. An efficient clinical nomogram based on PCDI and clinicopathological factors was then developed. PCDI was intimately associated with immunological attributes, and PCDI could efficaciously predict immunotherapy response. Additionally, the PCDI could predict the chemotherapy sensitivity of HCC patients. A multilevel panorama of PCDI genes confirmed its stability and credibility. Finally, the knockdown of GBA could suppress both the proliferative and invasive capacities of HCC cells.ConclusionThis study systematically elucidated the association between PCD and HCC. A robust PCDI was constructed for prognosis and therapy response prediction, which would facilitate clinical management and personalized therapy for HCC.

Background: Cuproptosis and necroptosis represent two distinct programmed cell death modalities implicated in neoplastic progression; however, the role of combining cuproptosis and necroptosis in hepatocellular carcinoma (HCC) remains to be elucidated.Methods: A total of 29 cuproptosis-related necroptosis genes (CRNGs) were identified, followed by an extensive analysis of their mutational characteristics, expression patterns, prognostic implications, and associations with the tumor microenvironment (TME). Subsequently, a CRNG subtype-related signature was developed, and its value of prognostic prediction, TME, and therapeutic responses in HCC were thoroughly investigated. Last, quantitative real-time PCR and Western blotting were employed for investigating the signature gene expression in 15 paired clinical tissue samples.Results: Two distinct CRNG subtypes were discerned, demonstrating associations between CRNG expression patterns, clinicopathological attributes, prognosis, and the TME. A CRNG subtype-related prognostic signature, subjected to external validation, was constructed, serving as an independent prognostic factor for HCC patients, indicating poor prognosis for high-risk individuals. Concurrently, the signature’s correlations with an immune-suppressive TME, mutational features, stemness properties, immune checkpoint genes, chemoresistance-associated genes, and drug sensitivity were observed, signifying its utility in predicting treatment responses. Subsequently, highly accurate and clinically convenient nomograms were developed, and the signature genes were validated via quantitative real-time PCR and Western blotting, further substantiating the stability and dependability of the CRNG subtype-related prognostic signature.Conclusion: Overall, this investigation presented an extensive panorama of CRNGs and developed the CRNG subtype-related prognostic signature, which holds potential for implementation in personalized treatment strategies and prognostic forecasting for HCC patients.

The development of liver fibrosis primarily determines quality of life as well as prognosis. Animal models are often used to model and understand the underlying mechanisms of human disease. Although organoids can be used to simulate organ development and disease, the technology still faces significant challenges. Therefore animal models are still irreplaceable at this stage. Currently, in vivo models of liver fibrosis can be classified into five categories based on etiology: chemical, dietary, surgical, transgenic, and immune. There is a wide variety of animal models of liver fibrosis with varying efficacy, which have different implications for proper understanding of the disease and effective screening of therapeutic agents. There is no high-quality literature recommending the most appropriate animal models. In this paper, we will describe the progress of commonly used animal models of liver fibrosis in terms of their development mechanisms, applications, advantages and disadvantages, and recommend appropriate animal models for different research purposes.

TPS375 Background: In normal conditions, Claudin (CLDN)18.2 is a tight junction protein with expression strictly confined to differentiated epithelial cells in gastric mucosa. CLDN18.2 has been found to be upregulated, and involved in tumor development and progression in a variety of tumor types such as gastric, pancreatic, and bile duct cancer (BTC). The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development. IMAB362 is the first anti-CLDN18.2 monoclonal antibody (mAb) of high potency to have been tested in humans and it revealed clinical efficacy in gastric cancer in a phase II study. TST001, a humanized IgG1 mAb, binds to a distinct epitope of CLDN18.2 with higher affinity and mediates CLDN18.2 expressing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) in comparison with IMAB362; Furthermore, TST001 is produced using an optimized glycoengineering process to increase affinity to FcR. The enhanced binding to CLDN18.2 on tumor cells and FcR on NK cells results in more efficient engagement of the tumor cells with NK cells and antibody mediated cellular cytotoxicity. In preclinical xenograft studies, TST001 displayed potent anti-tumor activities in the tumor models with medium to high level of CLDN18.2 expression and synergy anti-cancer effect with checkpoint inhibitor. A mAb specific for CLDN18.2 was also developed as an IHC based biomarker for patient enrollment in the clinical trials. Methods: This is an open-label, multi-center, phase I clinical trial to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK) profile and preliminary anti-cancer effect of TST001 in patients with locally advanced or metastatic solid tumors. (NCT04396821) The study consists of two parts: Part A is a 3+3 dose escalation design with sequential dose cohorts of 1, 3, 6, 10mg/kg in Q2W and Q3W schedules. Based on the emerging safety data, higher doses may be proposed for testing. About 27-54 patients will be enrolled. Dose expansion (Part B) will utilize doses of TST001 based on the emerging data from Part A. In Part B, up to 20 patients with CLDN18.2 overexpression per tumor specific cohort will be enrolled to 3 cohorts: A: TST001 single agent in gastric/gastroesophageal junction (G/GEJ) cancer; B: TST001 + nivolumab in G/GEJ cancer; C: TST001 single agent in pancreatic cancer or BTC. All patients in Part B will be selected by CLDN18.2 expression by central lab testing. The safety, anti-tumor activity, and PK will be further assessed in Part B. Enrolment began in July 2020 in the USA and is ongoing in multiple sites. As of 20 September, 2021, 23 subjects were dosed in Part A and the dose of 10mg/kg is being tested. Another phase I study of TST001 single agent and in combination with chemotherapy in patients with metastatic solid tumor is also ongoing in China (NCT04495296).

Additional file 8. Table S6. List of signature genes expressed in B cell subclusters, Related to Figure 4.

Background The intricate landscape of immunocytes in the tumor microenvironment (TME) is fundamental to immunotherapy but notably under-researched in extrahepatic cholangiocarcinoma (ECCA). Methods Single-cell RNA sequencing technology was conducted to make an in-depth analysis of immunocytes from matched tumor tissues, paratumor tissues and peripheral blood from ECCA patients. The potential cellular interactions between two cell populations were analyzed with software CellPhoneDB (v2.1.7). Results We obtained 13526 cells and characterized the transcriptomes and heterogeneity of different clusters and subclusters of immunocytes from ECCA, including CD4+ T cells, CD8+ T cells, B cells and myeloid immunocytes. We observed the rarely described immunocyte subclusters "intermediate" exhausted CD8+ T (CD8+ Tex) cells and “nonclassic” plasmacytes (CD27+ CD138+ CD38−). In addition, we identified potential immunotherapy targets, for example, ACP5, MAGEH1, TNFRSF9 and CCR8 for Tregs and MT1 for CD8+ Tex cells. We also found strong cellular interactions among Treg cells, M2 macrophages and CD8+ Tex cells through ligand–receptor analysis, implying that potential cellular cross-linkage promoted the immunosuppressive nature of the TME. Conclusions In a word, our study illuminated the components of the TME and revealed potential cellular interactions at the individual cellular level in ECCA, we aimed to provide a new perspective for further immunological studies and immunotherapy of ECCA.

Abstract Background Hepatocellular carcinoma (HCC) is the second major cause of tumor death worldwide, threatening people's lives and health. Circulating tumor cells (CTCs) facilitate the progression of many cancers, including HCC. Methods Combining transcriptomic data from TCGA, ICGC and ctcRbase databases, we characterized differentially expressed circulating tumor cells/microemboli (CTCs/CTMs) related genes (CRGs). These differentially expressed CRGs were then analyzed with a lasso and multivariate COX, and a five-gene prognostic signature was constructed. Then, the prognostic signature was validated in the ICGC dataset and GES14520 dataset with survival analysis and receiver operating characteristic analysis. The immune infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE), and somatic mutation rate were also compared between the high- and low-risk groups to further evaluate the immunotherapeutic value of the model. Molecular subtypes of HCC were characterized by the non-negative matrix factor decomposition method (NMF), and potential compounds were evaluated for different subtypes. Nomograms were constructed to forecast the prognosis of patients. Comparison with other six models to assess the superiority of the CRGS signaturte. Result We constructed the prognostic characteristics of five CRGs (including CDCA8, TP53I3, MYCN, HAVCR1, and TXNRD1) and identified two HCC subtypes, C1 and C2. Patients in the low-risk group had a better survival time compared to the high-risk group. And patients in the high-risk group were associated with higher TMB, immune infiltration, somatic mutation rates, and lower TIDE scores. This prognostic profile was validated in the ICGC and GSE14520 datasets and had good predictive performance. Conclusion We have studied the perspective of CTC-related genes and developed a new prognostic signature to predict the prognosis of HCC patients. This signature with good performance will help to assess the prognosis of patients and may provide new insights for clinical management strategies.