Recurrence remains a major cause of failure after curative-intent therapy for hepatocellular carcinoma (HCC), including resection, ablation, and liver transplantation. Current surveillance relies on imaging and serum biomarkers, but radiologic relapse may lag behind biological recurrence. This gap has focused attention on circulating tumor DNA (ctDNA) and related cell-free DNA (cfDNA) approaches as candidate tools for minimal residual disease (MRD) assessment and molecular surveillance. In HCC, however, recurrence is biologically heterogeneous. Post-treatment relapse may arise from residual malignant clones, occult intrahepatic spread, or de novo hepatocarcinogenesis in a chronically injured liver. This complexity shapes assay selection, result interpretation, and the need for multimodal risk assessment. Tumor-informed ctDNA assays are best suited to tracking residual clonal disease, whereas methylation-based and composite cfDNA approaches may also capture low-shedding disease and recurrence-prone liver-field biology. Available studies suggest that postoperative ctDNA positivity, persistent serial positivity, rising molecular burden, and selected high-risk methylation signals are associated with recurrence risk after curative-intent therapy. Yet the evidence base is uneven across treatment settings and assay classes, laboratory methods are not yet standardized, and binary detectable-versus-undetectable reporting is rarely sufficient for clinical interpretation. The central translational question is therefore how ctDNA/cfDNA information should be used in realistic HCC surveillance pathways. Current evidence supports these assays as adjunctive molecular risk signals, not as standalone treatment triggers. This review synthesizes the evidence, compares assay strategies, outlines multimodal implementation barriers including standardization and cost, and proposes a cautious roadmap for ctDNA-guided recurrence surveillance in HCC.

Introduction: Hepatocellular carcinoma (HCC) has posed a serious threat to public health worldwide over the past decades. Despite advances in surgery, targeted therapy, and immunotherapy, the prognosis of patients with HCC remains poor. Therefore, more accurate prognostic models are urgently needed. Objective: To explore the relationship between hypoxia and HCC and construct a hypoxia-related gene prognostic model. To predict the overall survival of HCC patients by our model. Methods: Gene set variation analysis (GSVA) was performed using the GSE14520 dataset to identify the Hallmark gene set most strongly associated with the prognosis of HCC patients. A hypoxia-related gene (HRG) signature was then established and validated through multiple bioinformatics approaches. Gene set enrichment analysis was conducted to explore the potential signaling pathways associated with this novel five-gene HRG signature. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the expression of the five HRGs in HCC patients. Results: GSVA identified the hypoxia Hallmark gene set as the factor most significantly correlated with HCC prognosis. A novel five-gene HRG signature was developed and validated across datasets. The area under the curve values for predicting 1–5-year survival were consistently >0.7. Both the five-gene HRG signature and tumor–node–metastasis (TNM) stage were independent prognostic factors in The Cancer Genome Atlas and GSE14520 cohorts. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment in cell cycle, fatty acid metabolism, and peroxisome proliferator-activated receptor signaling pathways. qRT-PCR results indicated that most HRGs (except Lactate Dehydrogenase A (LDHA)) were differentially expressed between HCC and adjacent normal tissues. Conclusion: We constructed and validated a novel five-gene HRG signature and a prognostic nomogram. Combining this HRG signature with TNM stage improved the accuracy of prognostic prediction for HCC patients.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer deaths globally. Although considerable progress has been made in the treatment, clinical outcomes of HCC patients are still poor. Therefore, it is necessary to find novel prognostic factors upon which prevention and treatment strategies can be formulated. Ficolin-3 (FCN3) protein is a member of the human ficolin family. It activates complement through pathways associated with mannose-binding lectin-associated serine proteases. Herein, we identified that FCN3 was downregulated in HCC tissues and decreased FCN3 expression was closely related to poor prognosis. Overexpression of FCN3 induced apoptosis and inhibited cell proliferation via the p53 signaling pathway. Mechanistically, FCN3 modulated the nuclear translocation of eukaryotic initiation factor 6 (EIF6) by binding ribosome maturation factor (SBDS), which induced ribosomal stress and activation of the p53 pathway. In addition, Y-Box Binding Protein 1 (YBX1) involved in the transcription and translation level regulation of FCN3 to SBDS. Besides, a negative feedback loop in the downstream of FCN3 involving p53, YBX1 and SBDS was identified.

Hepatocellular carcinoma (HCC) is one of the dominating tumors causing death due to lack of timely discovery and valid treatment. Abnormal increase of Rac GTPase activating protein 1 (RACGAP1) has been verified to be an oncogene in plenty tumors. The profound mechanism of RACGAP1 was rarely reported in HCC. In this study, we explored the function and mechanism of RACGAP1 in HCC through multiple analysis and experiments. RACGAP1 expression was up-regulated in HCC samples and the high expression of RACGAP1 was an independent prognostic risk factor for HCC patients. Meanwhile, RACGAP1 promoted developments of HCC both in vitro and in vivo. We verified that RACGAP1 promoted proliferation of HCC via PI3K/AKT/CDK2 and PI3K/AKT/GSK3β/Cyclin D1 signaling pathway. RACGAP1 accelerated the invasion and metastasis of HCC via phosphorylation of GSK3β and nuclear translocation of β-catenin. Furthermore, by luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay, we confirmed Recombinant GA Binding Protein Transcription Factor Alpha (GABPA) regulated the transcription of RACGAP1. All these findings revealed that RACGAP1 promotes the progression of HCC through a novel mechanism, which might be a new therapeutic target for HCC patients.

Non-alcoholic steatohepatitis (NASH) is the major form of chronic liver disease in adults; however, there are no approved drugs for NASH. In this study, we designed the PNM-G-PV method, in which gelatin nanoparticles (G) are loaded with pioglitazone and vitamin E (G-PV) and then encapsulated by the surfaces of platelet-neutrophil hybrid membranes (PNM). Inherited from the natural source cells, the PNM show immune evading ability due to the surface marker comprising a number of "do not eat me" signals and has dual inflammatory enrichment capabilities due to specific surface adhesion molecules. By functionalizing the gelatin nanoparticle biomimetic surfaces, PNM-G can enhance the targeting to inflammatory sites and enrich liver tissue. The high expression of matrix metalloproteinase-9 (MMP-9) at the NASH site enables the gelatin nanoparticles to intelligently respond to degradation and then release vitamin E and pioglitazone for drug treatment. We performed an in vivo analysis of these nanoparticles to monitor changes in triacylglycerol metabolism in liver tissues and assessed the therapeutic efficacy of PNM-G-PV in a NASH rat model. The results showed that PNM-G-PV exhibited better therapeutic efficacy than therapies using G-PV or PV alone. This work explores a new biomedical use of PNM-G-PV and a promising NASH treatment protocol based on a new drug delivery system.

Background and Aims: Hepatocellular carcinoma (HCC) is a common malignant disease with high morbidity and mortality throughout the world. While Borealin is a putative oncogene that is dysregulated in multiple tumors, its exact role in HCC remains less investigated. Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) assays were employed to examine the relative amount of Borealin. Gene set enrichment analysis (GSEA) and other bioinformatic analyses were implemented to probe into the potential functions of Borealin. The biological roles and mechanisms of Borealin in the tumorigenesis and development of HCC were further evaluated using a battery of functional assays in vivo and in vitro. Results: Borealin was enhanced in the HCC tissue samples and hepatoma cells when compared with the nontumor tissues and normal liver cells. Higher Borealin expression was positively linked with advanced pathological phenotypes and inferior overall survival. The overexpression of Borealin promoted the cells' abilities on proliferation, invasion and epithelial-mesenchymal transition (EMT) in vitro, facilitated tumor growth and lung metastasis in vivo, whereas the silencing of Borealin inhibited these capabilities in vitro. Furthermore, Borealin interacted with beta-catenin and further activated the Wnt/beta-catenin signaling pathway, which endowed HCC cells with highly aggressive and metastatic capabilities. Conclusion: Borealin was identified as an oncogene that could promote HCC growth and metastasis by activating the WNT/beta-catenin signaling pathway. These findings extended the understanding of Borealin in HCC tumorigenesis and development and highlighted the significance of Borealin in HCC diagnosis and treatment.

Background: Hepatocellular carcinoma (HCC) is one of the most common challenges for public health worldwide. Due to its complex molecular and great heterogeneity, the effectiveness of existing HCC risk prediction models is unsatisfactory. Hence, more accurate prognostic models are pressingly needed. Materials and methods: Differentially expressed mRNAs (DEMs) between HCC and normal tissues were identified after downloading GSE1450 from gene omnibus (GEO) database. We randomly divided all patients into training and testing sets. Univariate Cox regression, lasso Cox regression and multivariable Cox regression analysis were used to constructed the prognostic gene signature in training set. Our study utilized Kaplan-Meier plot, time-dependent receiver operating characteristic (ROC), multivariable Cox regression analysis with clinical information, nomogram and decision curve analysis (DCA) to evaluate the predictive ability for overall survival of the novel gene signature in training, testing and whole sets. We also validated the prognostic capacity of the five-gene signature in an external validation set. The information of mutation of each gene was explored on cBioPortal online website. We performed gene set enrichment analysis (GSEA) to explore underlying mechanisms in the high and low risk group. Finally, quantitative real-time PCR was conducted to validate the expression tendency between 12 paired HCC and adjacent normal tissues. Results: Our study constructed a novel five-gene signature (CNIH4, SOX4, SPP1, SORBS2 and CCL19) for predicting overall survival of HCC. Time-dependent ROC curve indicated admirable ability in survival prediction in two datasets. Multivariable Cox regression analysis indicated that both this five-gene signature and TNM stage were two independent prognostic factors for overall survival of HCC patients. Combined with TNM stage clinical pathological parameters, the predictive capacity of nomogram had a decent improvement. The mutation of the five genes had no obvious variation. Plenty pathways were enriched by GSEA, including cell cycle and various metabolism. Furthermore, the mRNA levels of these five genes had significantly different expressions between HCC tissues and adjacent normal tissues by quantitative real-time PCR. Conclusions: A five-gene prognostic model and nomogram were constructed and validated for predicting prognostic of HCC patients. And the five-gene risk score with TNM stage models might help various HCC patients to customize individual therapies.

Emerging evidence has shown that aberrant expression of lncRNA-TP53TG1 plays important roles in various malignancies. However, the biological functions of lncRNA-TP53TG1 in hepatocarcinogenesis, as well as the underlying mechanisms, remain largely unknown. Here, we assessed whether lncRNA-TP53TG1 plays a key role in the progression of hepatocellular carcinoma (HCC). The expression of lncRNA-TP53TG1 was significantly decreased in HCC tissues and cells. Decreased expression of lncRNA-TP53TG1 was associated with aggressive clinical phenotypes and a poor prognosis. Ectopic expression of lncRNA-TP53TG1 inhibited hepatoma cell proliferation and migration in vitro and in vivo, whereas lncRNA-TP53TG1 knockdown exerted the opposite effects. Furthermore, lncRNA-TP53TG1 played an important role in slowing the epithelial-mesenchymal transition (EMT) process in HCC. Mechanistically, lncRNA-TP53TG1 physically interacted with PRDX4 and promoted its ubiquitin-mediated degradation, resulting in the inactivation of the WNT/β-catenin signaling pathway in hepatoma cells. Our findings demonstrate a novel mechanism by which lncRNA-TP53TG1 exerts its tumor-suppressive effects through the WNT/β-catenin signaling pathway in a PRDX4-mediated manner in HCC. Based on these results, lncRNA-TP53TG1 potentially represents a prognostic indicator and therapeutic target for patients with HCC.

Background: An iatrogenic bile duct injury (IBDI) is a severe complication that has a great impact on the physical and mental quality of life of the patients, especially for patients with postoperative benign biliary stricture. The effective measures for end-to-end biliary-to-biliary anastomosis intraoperative are essential to prevent the postoperative bile duct stricture, but also a challenge even to the most skilled biliary tract surgeon. Objective: A postoperative benign biliary stricture is an extremely intractable complication that occurs following IBDI. This study aimed to introduce a novel end-to-end biliary-to-biliary anastomosis technique named fish-mouth-shaped (FMS) end-to-end biliary-to-biliary reconstruction and determine the safety and effectiveness for preventing the postoperative benign biliary stricture in both rats and humans. Methods: In this study, 18 patients with biliary injury who underwent an FMS reconstruction procedure were retrospectively analyzed. Their general information, disease of the first hospitalization, operation method, and classification of bile duct injury (BDI) were collected. The postoperative complications were evaluated immediately perioperatively and the long-term complications were followed up at the later period of at least 5 years. An IBDI animal model using 18 male rats was developed for animal-based evaluations. A bile duct diathermy injury model was used to mimic BDI. The FMS group underwent an FMS reconstruction procedure while the control group underwent common end-to-end biliary-to-biliary anastomosis, a sham operation group was also established. The blood samples, liver, spleen, and common bile duct tissues were harvested for further assessments. Results: In the retrospective study, there was no postoperative mortality and no patient developed cholangitis during the 5-years postoperation follow-up. In the study of IBDI animal models, compared with the control group, the FMS reconstruction procedure reduced the occurrence of benign biliary stenosis, liver function damage, and jaundice. The blood tests as well as morphological and pathological observations revealed that rats in the FMS reconstruction group had a better recovery than those in the control group. Conclusions: An FMS reconstruction procedure is a safe and efficient BDI treatment method.

Hepatocellular carcinoma (HCC) is a common digestive tumor with high fatality worldwide. Previous studies have shown that Reticulocalbin-2 (RCN2) was a crucial factor for HCC proliferation, but invasion and migration mechanism of RCN2 contributing to HCC is poorly investigated. In this study, we estimated the RCN2 expression in both patient tissues and cell lines by polymerase chain reaction (PCR) and western blotting (WB), as well as the clinical information of HCC patients from public databases. Biological function induced by RCN2 in vitro and vivo was also researched through multiple functional experiments. Upstream and downstream signal of RCN2 was identified by bioinformatics. We found that up-regulated RCN2 was related to poorer prognosis in HCC patients and attached significance to HCC proliferation, invasion and migration. Luciferase reporter assay and chromatin immunoprecipitation validated that YY1 as the upstream transcription factor of RCN2, facilitating the expression of RCN2. Gene set enrichment analysis indicated that HCC progression induced by RCN2 might be related to MYC signaling. Further-more, we demonstrated RCN2 reduced proteasomal degradation of MYC and lead to HCC progression. The effects of overexpressed RCN2 in HCC were attenuated by MYC silencing. In conclusion, our study highlighted the vital role of RCN2 in tumor progression and the potential benefit for the treatment of HCC.

ABSTRACT:Hepatocellular carcinoma (HCC) is 1 of the deadliest malignancies worldwide. Despite significant advances in diagnosis and treatment, the mortality rate from HCC persists at a substantial level. Construction of a prognostic model that can reliably predict HCC patients' overall survival is urgently needed.Two RNA-seq dataset (the Cancer Genome Atlas and International Cancer Genome Consortium) and 1 microarray dataset (GSE14520) were included in our study. RNA-binding proteins (RBPs) in HCC patients was examined by differentially expressed genes analysis, functional enrichment analysis and protein-protein interaction network analysis. Subsequently, the Cancer Genome Atlas dataset was randomly divided into training and testing cohort with a prognostic model developed in the training cohort. In order to evaluate the prognostic value of the model, a comprehensive survival assessment was conducted.Five RBPs (ribosomal protein L10-like, enhancer of zeste homolog 2 (EZH2), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), zinc finger protein 239, interferon-induced protein with tetratricopeptide repeats 1) were used to construct the model. The model accurately predicted the prognosis of liver cancer patients in both the training cohort and validation cohort. HCC patients could be assigned into a high-risk group and a low-risk group by this model, and the overall survival of these 2 groups was significantly different (P  < .05). Furthermore, the risk scores obtained by this model were highly correlated with immune cell infiltration.The prognostic model helps to identify HCC patients at high risk of mortality, which optimizes decision-making for individualized treatment.

BackgroundTransmembrane protein 88 (TMEM88) has emerged as a newly discovered cancer-related protein that acts as a cancer-promoting or cancer-inhibiting regulator in multiple tumor types. However, the exact role of TMEM88 in liver cancer is undetermined. The current study was designed to determine the expression of TMEM88 in liver cancer. ResultsTMEM88 expression was significantly lower in several human cancers, but higher in liver and bile cancer, than in corresponding normal tissues. TMEM88 expression in HCC tissues correlated with prognosis. Low TMEM88 expression associated with poorer overall survival, disease-specific survival, progression-free survival, and relapse-free survival in multiple cohorts of HCC patients, particularly at late disease stages (grade 2 and 3). TMEM88 showed strong correlation with tumor-infiltrating B cells, CD4+ and CD8+ T cells, macrophages, neutrophils, and dendritic cells. ConclusionThese findings demonstrate that TMEM88 is a potential prognostic biomarker that determines cancer progression and correlated with tumor immune cells infiltration in HCC.

Hepatocellular carcinoma (HCC) remains hard to diagnose early and cure due to a lack of accurate biomarkers and effective treatments. Hence, it is necessary to explore the tumorigenesis and tumor progression of HCC to discover new biomarkers for clinical treatment. We performed weighted gene co-expression network analysis (WGCNA) to explore hub genes that have high correlation with clinical information. In this study, we found 13 hub genes (GTSE1, PLK1, NCAPH, SKA3, LMNB2, SPC25, HJURP, DEPDC1B, CDCA4, UBE2C, LMNB1, PRR11, and SNRPD2) that have high correlation with histologic grade in HCC by analyzing TCGA LIHC dataset. All of these 13 hub genes could be used to effectively distinguish high histologic grade from low histologic grade of HCC through analysis of the ROC curve. The overall survival and disease-free survival information showed that high expression of these 13 hub genes led to poor prognosis. Meanwhile, these 13 hub genes had significantly different expression in HCC tumor and non-tumor tissues. We downloaded GSE6764, which contains corresponding clinical information, to validate the expression of these 13 hub genes. At the same time, we performed quantitative real-time PCR to validate the differences in the expression tendencies of these 13 hub genes between HCC tumor tissues and non-tumor tissues and high histologic grade and low histologic grade. We also explored mutation and methylation information of these 13 hub genes for further study. In summary, 13 hub genes correlated with the progression and prognosis of HCC were discovered by WGCNA in our study, and these hub genes may contribute to the tumorigenesis and tumor progression of HCC.

•Circulating exosomal microRNAs provide new opportunities to unlock the secrets of hepatocellular carcinoma.•Both serum exosomes-encapsulated microRNAs and combined with traditional biomarkers improve diagnosis methods.•Strategies target exosomal microRNAs offer new tactics for treatment of hepatocellular carcinoma.

Hepatocellular carcinoma(HCC) is a malignant tumor with high mortality due to lack of early diagnostic methods and effective treatments, and the molecular mechanisms are intricate and remain unclear. In the present study, the role of macrophage receptor with collagenous structure (MARCO) in tumor advancement of HCC was investigated. We examined expression level of MARCO in HCC samples, corresponding adjacent nontumor tissues and six hepatoma cell lines by polymerase chain reaction and immunohistochemistry (IHC). Clinical information of HCC patients was also analyzed. The role of MARCO involved in HCC progression via multiple functional experiments in vitro and in vivo was investigated. Bioinformatics analysis was conducted to further explore biological functions of MARCO. We found MARCO was suggestively down-regulated in HCC and associated with favorable prognosis, and MARCO upregulation oppressed tumor cell migration and invasion. Besides, overexpression of MARCO not only promoted apoptosis of hepatoma cells but also suppressed proliferation in vivo and in vitro. Furthermore, gene set enrichment analysis (GSEA) analysis suggested that MARCO may be related to the P53 signaling pathway, and this prediction was confirmed in this study as well. In sum, our study indicated that MARCO was involved in HCC progression and it can be defined as a novel probable biomarker as well as treatment target for HCC.

Objective To analyze the expression of YTH domain containing family 2 (YTHDF2) in the hepatocellular carcinom (HCC) and the relationship between the expression of YTHDF2 and prognosis.To detect the influence of YTHDF2 in cell proliferation,migration and invasion.Methods We detected the expression of YTHDF2 among the paired HCC tissue and adjacent tumor tissue with bioinformatics,real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) and immunohistochemistry.To analyze the relationship between YTHDF2 expression and clinical characteristics.We established the HCC cells with YTHDF2 knockdown and analyzed the cell proliferation with cell counting kit-8 (CCK-8) assay and detect the cell migration with Transwell and wound scratch assay.To analyze the expression of E-cadherin and N-cadherin that associated with epithelial-mesenchymal transition (EMT) with western blotting.Results Bioinformatics analysis showed the high expression of YTHDF2 in HCC tumor and its relationship with poor prognosis.We found that the HCC tumor tissue has a higher expression of YTHDF2 in compared with non-tumor adjacent tissue (17.76 ± 4.78 vs.12.10 ± 3.43,P ＜ 0.01).The expression of YTHDF2 is positively related with BCLC stage,TNM stage and portal vein tumor thrombosis (PVTT) (P ＜0.01).CCK-8 assay demonstrated that the absorbance at 450 nm of the cell with YTHDF2 knockdown is lower than the negative control,while HepG2 is (1.129 ± 0.178 vs.1.571 ± 0.226,P ＜ 0.01) and Huh7 (1.227 ± 0.251 vs.1.815 ± 0.302,P ＜ 0.05).Transwell assay showed that the number of cell that diffuses through the membrane of cell with YTHDF2 knockdown is lower than the negative control.The wound scratch assay showed that the percent of wound area in cell with YTHDF2 knockdown is lower.We detected the HCC cells with YTHDF2 konckdown and found it had a higher relative expression of E-cadherin (1.780 ± 0.319 vs.0.916 ± 0.173,P ＜ 0.05) and a lower expression of N-cadherin (0.821 ±0.217 vs.4.697 ±0.398,P＜0.01).Conclusion The high expression of YTH-DF2 in HCC tissue showed its relationship with HCC development and YTHDF2 may play an important role in HCC cell proliferation and migration.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors throughout the world. However, its mortality rate remains very high due to the absence of early diagnostic modalities and effective treatments, and its specific pathogenesis remains unclear. Here, we investigated the role of PNMA1 in the tumorigenesis of HCC. We found that PNMA1 was significantly upregulated in HCC. Clinically, higher expression of PNMA1 was associated with aggressive phenotypes and poor prognosis. Functionally, silencing of PNMA1 repressed proliferation in vitro and in vivo, and knockdown of PNMA1 suppressed tumor cell migration and invasion. Via GSEA analysis, we predicted that PNAM1 may be related to the epithelial-mesenchymal-transition and the Wnt signaling pathway. Both these assumptions were confirmed in our study. Furthermore, we proved that miR-33a-5p participated in the posttranscriptional regulation of PNMA1. Together, our findings suggested that PNMA1 participated in HCC progression and may be a potential biomarker and therapeutic target for HCC.

Objective: We conducted a network meta-analysis to comprehensively compare various anticancer agents used in transarterial chemoembolization (TACE) based on the Bayesian theorem.Methods: Globally recognized electronic databases, including PubMed, EMBASE, and Cochrane Central, were searched to retrieve relevant randomized controlled trials (RCTs) comparing anticancer agents in TACE for hepatocellular carcinoma (HCC) patients. The therapeutic response, adverse events and overall survival rate were selected as parametric data to evaluate the clinical efficacy. Quantitative network meta-analysis and pair-wise analysis were conducted to compare the relative parameters.Results: Of the 4242 retrieved articles, 17 RCTs containing 2330 patients fulfilled the inclusion criteria. The network meta-analysis exhibited that the application of anthracycline and mitomycin plus pyrimidine presented the best clinical values regarding all parametric data (probability P=0.45, 0.32 and 0.35 regarding comparison of response rate, adverse event and overall survival, respectively). Accordingly, further investigation on specific anticancer agents indicated that the combination of doxorubicin and mitomycin plus gemcitabine was the best agent combination in TACE (probability P=0.49, 0.37 and 0.77 regarding comparison of response rate, adverse event and overall survival, respectively). Moreover, an additional study indicated that the single use of an anticancer agent prior to embolism brought no benefit compared with bland embolism without any agent (Test Z=0.15, 0.84, 1.22 and P=0.88, 0.40, 0.22 regarding comparison of response rate, adverse event and overall survival, respectively). However, the combined use of anticancer agents in TACE showed significantly better clinical efficacy than single use (Test Z=4.40, 3.94, 0.24 and P<0.001, <0.001, =0.81 regarding comparison of response rate, adverse event and overall survival, respectively); thus, combination utilization was recommended.Conclusions: The combined use of anticancer agents in TACE was recommended. Application of anthracycline and mitomycin plus pyrimidine seemed to be the best choice for clinical consideration. Additionally, the combination of doxorubicin and mitomycin plus gemcitabine may be the best specific anticancer agent combination in TACE currently, although additional RCTs are expected to support our conclusion.