Bufalin is a potent bioactive compound extracted from the venom of toads such as Bufo gargarizans. It has rich pharmacological effects, and its traditional applications mainly include anti-cancer, anti-inflammatory and analgesic, especially in cancer treatment, which has been a hot topic of research. Prior research has suggested that bufalin may have anti-tumor angiogenic effects. However, the efficacy and mechanism of bufalin inhibiting hepatocellular carcinoma (HCC) angiogenesis have yet to be further investigated.

An extensive detailed strategy via network pharmacology, proteomics, histopathological analysis, molecular docking, in vitro experiments, and in vivo magnetic resonance imaging (MRI) examinations were adopted to investigate the efficacy and mechanisms of bufalin against HCC angiogenesis.

Micro-vessel density (MVD) and intravoxel incoherent motion (IVIM) perfusion-related parameters based on magnetic resonance diffusion-weighted imaging were used to identify the effect of bufalin against HCC angiogenesis. Potential bufalin and HCC targets were gathered from appropriate databases. The STRING database was used to construct the target protein interaction networks. The "clusterprofiler" package (version 4.2.2) in R was applied to conduct the target-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. Network pharmacology and proteomics were integrated to identify key targets and pathways related to bufalin against HCC angiogenesis. Molecular docking and Western Blot were utilized to validate the findings.

Analysis through IVIM and MVD showed that bufalin could inhibit HCC angiogenesis in nude mice models. A total of 159 common targets of bufalin and HCC were identified by network pharmacology. GO analysis revealed that these targets focused on multiple angiogenesis-related biological processes, including endothelial cell proliferation and migration, sprouting angiogenesis, and regulation of angiogenesis. The KEGG enrichment results suggested that bufalin could regulate multiple signaling pathways to inhibit HCC angiogenesis, including VEGF, MAPK, PI3K-Akt, mTOR, and HIF-1 signaling pathways. MAPK1, MAPK14, PRKCA, EIF4E, and APEX1 might be critical targets in regulating the above pathways. The molecular docking and Western blot analysis verified the effects of bufalin on target proteins.

This study demonstrated that bufalin might inhibit HCC angiogenesis by regulating multiple targets and pathways. These findings offer theoretical insights and experimental foundations for the clinical application and commercial development of bufalin in the treatment of HCC.

An existing study has underlined the involvement of Methyltransferase Like 3 (METTL3) and its mediated N6-methyladenosine (m6A) modification on zinc finger MYM-type containing 1 (ZMYM1) in cancers, and we aimed to explore their implication in live hepatocellular carcinoma (LIHC). The levels of METTL3 and ZMYM1 in LIHC cells were gauged via qPCR. The involvement of METTL3 in LIHC progression was explored via assays in vitro and in vivo, and the mechanisms underlying the effects of METTL3 on LIHC were explored via m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) and confocal immunofluorescence assays. METTL3, the m6A methyltransferase of interest, expressed relatively higher in LIHC. The promoting effects of METTL3 on LIHC progression were confirmed both in vitro and in vivo, and the relevant mechanisms maybe related to ZMYM1, a target of METTL3. Such effects of METTL3-m6A-ZMYM1 axis on the progression of LIHC were confirmed to be related to the inactivation of RAS/ERK/c-FOS pathway and the reduction in E-cadherin expression yet the elevation in N-cadherin and Vimentin expressions, therefore accelerating the metastasis in LIHC. Our study highlighted the possible involvement of METTL3-mediated m6A modification in LIHC and explored METTL3-m6A-ZMYM1 axis as a possible therapeutic target for the anti-metastatic strategy against LIHC.

Tyrosine kinase inhibitors (TKIs) are first-line therapies for hepatocellular carcinoma (HCC), but the drug resistance restricts the long-term clinical outcomes. This study aimed to investigate the expression patterns and possible clinical significance of a TKI-resistant gene zeste white 10 (ZW10) in HCC.

Clustered regularly interspaced short palindromic repeats (CRISPR) screening was conducted to obtain TKI-resistant genes. Pan-cancer analysis was employed to analyze the expression landscape of the critical TKI-resistant gene ZW10. Transcriptional expression data for ZW10 were obtained from 76 centers, including 3,312 HCC samples and 2,703 noncancerous tissues. A summary receiver operating characteristic (SROC) curve was built to evaluate ZW10 expression characteristics in HCC. Unpaired two-sample Wilcoxon method was conducted to analyze ZW10 expression levels in HCC of various etiologies. Univariate Cox method was employed to assess the prognostic value of ZW10. Moreover, the gene function within HCC cell lines, the TKI treatment responses, key pathways, and tumor microenvironment of ZW10 were bioinformatically investigated. Drug prediction and molecular docking techniques were used to explore the potency of ZW10 as a novel therapeutic target.

The abundance of small guide RNA (sgRNA) corresponding to ZW10 gene was decreased in the whole genome CRISPR knockout library (LogFC = -1.19), indicating that ZW10 may participate in TKI resistance. The differential expression landscape of ZW10 was found in various malignancies including HCC, which was associated with poorer prognosis. Pooled standardized mean difference (SMD) of ZW10 mRNA expression was 0.47 (95% confidence interval (CI): 0.32 - 0.63), the area under SROC was 0.76 (95% CI: 0.72 - 0.79), the sensitivity was 0.63 (95% CI: 0.53 - 0.72), and the specificity was 0.77 (95% CI: 0.67 - 0.84). ZW10 was investigated significant for the growth of HCC cells. Nucleocytoplasmic transport was the possible pathway that ZW10 involved. High level of ZW10 was reversely associated with TKI responses and the abundance of immune cell infiltration. Mocetinostat and capecitabine were predicted to be the potential inhibitors targeting ZW10 with a minimum binding energy of -8.2 and -7.1 kcal/mol, respectively.

ZW10 is considered a TKI-resistant and tumor-supportive gene, which is also a promising novel prognostic biomarker for HCC or a therapeutic target for overcoming TKI resistance.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent the most prevalent primary liver cancers and pose significant challenges in oncology. While their etiology and incidence vary globally, the molecular landscape of these tumors is increasingly understood, offering new opportunities for precision medicine. In this joint multinational review, we present a comprehensive analysis of the key molecular pathways involved in the pathogenesis of HCC and CCA, highlighting actionable targets for emerging therapies. Recent advances in molecular diagnostics have significantly influenced treatment paradigms for both cancers. In HCC, while genetic alterations have not yet led to established diagnostic or therapeutic applications, targeting vascular endothelial growth factor (VEGF), immune checkpoints, and tyrosine kinase pathways has demonstrated considerable therapeutic potential. In CCA, genetic profiling has uncovered actionable alterations, such as FGFR2 fusions and IDH1 mutations, driving the development of targeted therapies. The growing complexity of precision oncology underscores the need for standardized molecular testing and streamlined diagnostic workflows to ensure timely and effective treatment. This review also emphasizes the importance of collaborative efforts between clinicians, pathologists, and oncologists to optimize outcomes. By synthesizing the latest molecular insights and treatment trends, this review provides a valuable resource to guide the personalized management of HCC and CCA.

To provide a reference for hepatocellular carcinoma (HCC) clinical trials, we analyzed HCC clinical trials and therapeutic targets.

Using the Informa database, we analyzed the global and China HCC clinical trials. We then explored TACE, Apatinib, and emerging strategies (CAR T/NK). Additionally, we analyzed the oncogenic biomarkers and therapeutic targets. We conducted a joint analysis of therapeutic target safety using HPA-RNA, HPA-Proteins, and GTEx-RNA datasets. Finally, we analyzed the specificity and prospects of therapeutic targets using HPA pathology data and CPTAC data.

HCC clinical trials have developed rapidly over the past decade but have now reached a bottleneck, with most breakthroughs focusing on combination therapies. China and the USA dominate in the number of trials. TACE combined with systemic therapy has become an effective treatment strategy for intermediate to advanced HCC. Apatinib and TACE combined with systemic therapy are characteristic of China, while the latter is also mainly conducted in Japan and the USA. Currently, targeted immune therapies dominate the field, and CAR T/NK still in the early stages. Most therapeutic targets are related to the VEGF pathway, which indirectly confirms the predominant role of TKI-ICI combination therapy in HCC treatment. Most targets have low safety and poor specificity. However, RRM2, KDR, and AURKA have strong safety and specificity, showing excellent prospects for targeted HCC therapy.

This study analyzed and summarized the overview of HCC clinical trials and the safety and specificity of therapeutic targets, providing a reference for HCC clinical research.

Neuropilin and tolloid-like 2 (NETO2) facilitates the progression of various cancers, but its role in hepatocellular carcinoma (HCC) is not known. This study aimed to assess the potential of targeting NETO2 in HCC and its relationship with the STAT3/C-MYC pathway.

HCC cells (Huh7 and MHCC-97 H) were cultured and transfected with control siRNA (siCtrl), NETO2 siRNA (siNETO2), control overexpression (oeCtrl), or NETO2 overexpression (oeNETO2), with non-transfected cells used as blank controls.

NETO2 mRNA and protein expressions were reduced in both Huh7 and MHCC-97 H cells. EdU and CCK-8 assays indicated that cell proliferation was decreased after siNETO2 transfection in Huh7 and MHCC-97 H cells. TUNEL assay found revealed that the cell apoptosis rate was greater after siNETO2 transfection in MHCC-97 H cells, and tended to be greater in Huh7 cells (but the difference was not statistically significant). Transwell invasion assay revealed that the number of invasive Huh7 and MHCC-97 H cells decreased after siNETO2 transfection. Cell scratch assay revealed that the cell migration rate was reduced after siNETO2 transfection in Huh7 cells but was not significantly different in MHCC-97 H cells. Western blotting revealed that p-STAT3 and C-MYC expressions were decreased after siNETO2 transfection in Huh7 and MHCC-97 H cells. Overexpression experiments revealed that cell proliferation and invasion were promoted but that the cell apoptosis rate was reduced after oeNETO2 transfection in Huh7 and MHCC-97 H cells.

NETO2 knockdown suppresses HCC cell proliferation, invasion, and migration and inactivates the STAT3/C-MYC pathway, suggesting that NETO2 is a potential target for HCC treatment.

Non-coding small RNA, specifically tRNA-derived small RNAs (tsRNAs), are readily detectable in cancer patients, exhibit remarkable stability, and are present in high abundance. They play a significant role in tumor development. However, the clinical significance of serum tsRNAs in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we explored the impact of a novel tsRNA, named tRF-23-R9J89O9N9, in the adjuvant diagnosis, disease monitoring, and prognosis assessment of HCC.

The tRF-23-R9J89O9N9 was identified as the target molecule through screening the The Cancer Genome Atlas(TCGA) database. Its expression levels were measured using qRT-PCR. Various methods, including agarose gel electrophoresis, Sanger sequencing, gradient dilution experiments, room temperature stability tests, and repeated freeze-thaw assessments, were employed to evaluate the performance of tRF-23-R9J89O9N9. The correlation between tRF-23-R9J89O9N9 levels and clinicopathological parameters was analyzed using the χ2 test. The diagnostic value of tRF-23-R9J89O9N9 in HCC was assessed with ROC curve analysis, while the prognostic value was evaluated using Kaplan-Meier curves.

Serum tRF-23-R9J89O9N9 expression levels were significantly elevated in HCC patients, while levels in postoperative patients were restored to those of healthy subjects. Additionally, the expression of tRF-23-R9J89O9N9 related to TNM stage(P = 0.009), lymph node metastasis(P＜0.0001), and degree of differentiation(P＜0.0001). Furthermore, the combination of AFP, PIVKA-II, and CEA greatly improved the diagnostic value for HCC. Serum tRF-23-R9J89O9N9 was also identified as a potential biomarker for dynamic monitoring and prognosis of HCC.

tRF-23-R9J89O9N9 may regard as a potential novel biomarker for the adjuvant diagnosis of HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with chronic infections by hepatotropic viruses such as hepatitis B virus (HBV), and hepatitis C virus (HCV), being major risk factors. Chronic infections with these viruses are the leading cause of HCC worldwide, with HBV alone responsible for over 50% of cases. Despite advances in direct-acting antivirals (DAAs) for HCV and nucleos(t)ide analogues (NAs) for HBV, challenges remain in HCC prevention, early detection, and treatment. Recent research highlights the role of viral-induced metabolic alterations, such as the Warburg effect, mitochondrial dysfunction, and lipid dysregulation, in promoting HCC. Moreover, immune checkpoint inhibitors have emerged as effective treatments for advanced HCC, though responses vary between HBV- and HCV-related cancers. Additionally, novel therapeutic approaches and metabolic-targeted therapies offer promising avenues for virus-associated HCC treatment. Advancements in liquid biopsy biomarkers and artificial intelligence-driven diagnostics are improving HCC surveillance and risk stratification, potentially enabling earlier interventions. While HBV vaccination has significantly reduced HCC incidence, disparities in global vaccination coverage persist. Furthermore, antiviral therapies combined with structured surveillance programs have proven effective in reducing HCC incidence and mortality. This review highlights the complex connection between viral, genetic, and environmental factors in HCC development and underscores the importance of integrated prevention strategies to reduce its burden globally.

Hepatocellular carcinoma (HCC) poses a serious threat to human health due to its high mortality rate. Recently, breakthrough progress has been made in immunotherapy field. However, the mechanisms underlying HCC progression and immune escape are still unclear. This study aimed to investigate the impact of brain-specific angiogenesis inhibitor 1-associated protein 2-like 2 (BAIAP2L2) in HCC and elucidate its potential mechanisms in this context. Clinical data revealed that the overexpression of BAIAP2L2 correlated with tumor progression and poor prognosis in HCC patients. Functional assays demonstrated that BAIAP2L2 facilitates HCC proliferation, metastasis, invasion, and PD-L1-mediated immune evasion both in vitro and in vivo. Mechanistically, we observed co-localization and interaction between BAIAP2L2 and JAK1 within HCC cells, in turn enhancing the activation of the JAK1/STAT3 signaling pathway. Utilizing the JAK1 inhibitor Ruxolitinib effectively reversed BAIAP2L2-induced cellular processes such as proliferation, migration, invasion, and PD-L1 upregulation. Overall, our results emphasize that BAIAP2L2 plays a crucial role in driving tumor progression and immune evasion in HCC through the JAK1-mediated signaling pathway, thus proposing BAIAP2L2 as a promising therapeutic target for HCC treatment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by a high rate of postoperative recurrence and poor long-term survival outcomes. Structural maintenance of chromosome 4 (SMC4) is frequently overexpressed in various types of cancer and plays a pivotal role in tumor cell growth, migration, and invasion. Bioinformatics analysis has revealed a significant correlation between the tumor-node metastasis (TNM) stage (P < 0.01) and SMC4 expression (P < 0.05), and SMC4 was associated with poor prognosis in HCC. Furthermore, SMC4 was identified as an independent prognostic factor for HCC. Ubiquitin-specific peptidase 39 (USP39) was found whether the regulation was observed to affect protein synthesis or stability through bioinformatics analysis and immunoprecipitation. The expression levels and cellular localization of SMC4 and USP39 in hepatoma cells were evaluated using quantitative real-time PCR (qPCR), western blotting, and immunohistochemistry (IHC), all of which indicated significantly elevated expression of USP39 and SMC4 in HCC. The roles of the SMC4/USP39 were further investigated through several assays, including the 3-(4,5-Dimethylthiazol-2-yl) -2,5- diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and wound healing assay. The results demonstrated that USP39/SMC4 plays a crucial role in enhancing the viability and proliferation of HepG2 cells. Additionally, bioinformatics analysis identified ZNF207 and TIAL1 as potential target proteins of SMC4. Drug-resistant hepatoma cell lines were established, and both MTT and EdU assays were performed to assess cell viability and proliferation. The results demonstrated that HepG2/5-FU cells regained their sensitivity to 5-FU following the knockdown of SMC4. Additionally, the knockdown of either TIAL1 or ZNF207 also restored 5-FU sensitivity in HepG2/5-FU cells, effectively inhibiting cell viability and proliferation. Our study underscores the significant role of the USP39/SMC4 in HCC development and suggests that SMC4 may contribute to the regulation of drug resistance in hepatoma cell lines, potentially through interactions with TIAL1 and ZNF207.

Serine/arginine-rich splicing factors (SRSFs) are a family of 12 RNA-binding proteins crucial for the precursor messenger RNA (pre-mRNA) splicing. SRSFs are involved in RNA metabolism events such as transcription, translation, and nonsense decay during the shuttle between the nucleus and cytoplasm, which are important components of genome diversity and cell viability. SRs recognize splicing elements on pre-mRNA and recruit the spliceosome to regulate splicing. In tumors, aberrant expression of SRSFs leads to aberrant splicing of RNA, affecting the proliferation, migration, and anti-apoptotic ability of tumor cells, highlighting the therapeutic potential of targeted SRSFs for the treatment of diseases. The body's immune system is closely related to the occurrence and development of tumor, and SRSFs can affect the function of immune cells in the tumor microenvironment by regulating the alternative splicing of tumor immune-related genes. We review the important role of SRSFs-induced aberrant gene expression in a variety of tumors and the immune system, and prospect the application of SRSFs in tumor. We hope that this review will inform future treatment of the disease.

Liver cancer ranks as the sixth most prevalent form of cancer and stands as the fourth leading cause of cancer-related fatalities on a global scale. The two primary types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). While ICC originates from the bile ducts, HCC develops from hepatocytes, which are the primary functional cells of the liver. In cases where liver cancer is detected in its early stages, it can be effectively treated through locoregional interventions such as surgical resection, Radiofrequency Ablation, Transarterial chemoembolization, or liver transplantation. However, HCC is typically diagnosed at advanced stages, rendering these treatment options ineffective due to the unresectable nature of the tumor. LncRNAs, a novel class of RNA molecules and epigenetic regulators, have emerged as key players in the development and advancement of different types of tumors. They exert their influence by regulating the expression of downstream genes in cancer-related signaling pathways, thereby promoting the proliferation, migration, and invasion of tumor cells. Additionally, these transcripts have the ability to modify the activity and expression of tumor suppressors and oncogenes, further contributing to tumorigenesis. Recently, growing numbers of experiments have demonstrated the elevated expression of HOX antisense intergenic RNA (HOTAIR), a spliced and poly-adenylated lncRNA, in liver cancers and its association with cancer patient's prognosis and overall survival, as well as tumor cells' growth, metastasis, and resistance to therapies. This updated review will summarize molecular pathways by which lncRNA HOTAIR promotes liver cancer development, and highlight its diagnostic and therapeutic potential, though.

Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied.

The cell viability, proliferation, and cuproptosis-related protein levels were detected to investigate whether EGCG enhances the sensitivity of HCC cells to cuproptosis. The intracellular copper level, related copper metabolism proteins, and gene expression were detected to explore the mechanisms. In addition, a nude mouse xenograft model was established to determine the effects of EGCG on cuproptosis in tumor tissues.

The combination of EGCG and copper ionophores significantly enhanced the mortality of HCC cells and heightened the sensitivity of HCC cells to cuproptosis. There was a notable reduction in the expression of copper export protein copper-transporting P-type ATPase (ATP7B). EGCG effectively suppressed metal regulatory transcription factor (MTF1) expression and subsequently hindered the transcriptional regulation of ATP7B. EGCG also facilitated the intratumoral accumulation of copper and augmented susceptibility to cuproptosis in vivo.

EGCG can increase the sensitivity of hepatocellular carcinoma cells to cuproptosis by promoting intracellular copper accumulation through the MTF1/ATP7B axis.

To evaluate the expression pattern of non-SMC condensin II complex subunit D3 (NCAPD3) in hepatocellular carcinoma (HCC) tissues, assess its association with clinical characteristics, and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms.

NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR. Patients were divided into high- and low-expression groups on the basis of NCAPD3 levels, and associations with clinical parameters were assessed. The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase (PI3K) agonist Y-P 740 on cell functions were examined via cell proliferation, Transwell migration, and invasion assays. Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing. Western blotting was performed to measure NCAPD3, AKT serine/threonine kinase 1 (AKT1), and phosphorylated AKT1 levels.

NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues. A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC. NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells. mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes. Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown.

Elevated NCAPD3 expression was strongly correlated with HCC metastasis. NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K-AKT signalling pathway.

The integration of exercise prescriptions into cancer adjuvant therapy presents challenges stemming from the ambiguity surrounding the precise mechanism through which exercise intervention mitigates the risk of hepatocellular carcinoma (HCC) mortality and recurrence. Elucidation of this specific mechanism has substantial social and clinical implications. In this study, tumor-bearing mice engaged in voluntary wheel running exhibited a notable decrease in tumor growth, exceeding 30%. Microarray analysis revealed an upregulation of cytokine-related pathways as a potential explanation for this effect. The inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to enhance tumor cell proliferation, while the absence of GM-CSF resulted in a marked inhibition of tumor cell growth. The findings suggest that exercise-induced serum from mice can impede the proliferation of mouse tumor cells, with the adipokine chemerin inhibiting the growth factor GM-CSF. Additionally, exercise was found to stimulate chemerin secretion by brown adipose tissue. Chemerin suppression led to a reduction in the inhibition of tumor cell proliferation. The results of this study suggest that exercise may stimulate the release of adipokines from brown adipose tissue, transport them through the blood to the distant tumor microenvironment, and downregulate GM-CSF expression, alleviating tumor immunosuppression in the tumor microenvironment, thereby inhibiting at HCC progression. These findings provide a theoretical basis for incorporating exercise prescription into cancer treatment.

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive forms of liver cancer, with high morbidity and poor prognosis due to late diagnosis and limited treatment options. Despite advances in understanding its molecular mechanisms, effective biomarkers for early detection and targeted therapy remain scarce. Zinc finger protein 71 (ZNF71), a zinc-finger protein, has been implicated in various cancers, yet its role in HCC remains largely unexplored. This gap in knowledge underscores the need for further investigation into the ZNF71 of potential as a diagnostic or therapeutic target in HCC.

To explore the expression levels, clinical relevance, and molecular mechanisms of ZNF71 in the progression of HCC.

The study evaluated ZNF71 expression in 235 HCC specimens and 13 noncancerous liver tissue samples using immunohistochemistry. High-throughput datasets were employed to assess the differential expression of ZNF71 in HCC and its association with clinical and pathological features. The impact of ZNF71 on HCC cell line growth was examined through clustered regularly interspaced short palindromic repeat knockout screens. Co-expressed genes were identified and analyzed for enrichment using LinkedOmics and Sangerbox 3.0, focusing on significant correlations (P < 0.01, correlation coefficient ≥ 0.3). Furthermore, the relationship between ZNF71 expression and immune cell infiltration was quantified using TIMER2.0.

ZNF71 showed higher expression in HCC tissues vs non-tumorous tissues, with a significant statistical difference (P < 0.05). Data from the UALCAN platform indicated increased ZNF71 levels across early to mid-stage HCC, correlating with disease severity (P < 0.05). High-throughput analysis presented a standardized mean difference in ZNF71 expression of 0.55 (95% confidence interval [CI]: 0.34-0.75). The efficiency of ZNF71 mRNA was evaluated, yielding an area under the curve of 0.78 (95%CI: 0.75-0.82), a sensitivity of 0.63 (95%CI: 0.53-0.72), and a specificity of 0.82 (95%CI: 0.73-0.89). Diagnostic likelihood ratios were positive at 3.61 (95%CI: 2.41-5.41) and negative at 0.45 (95%CI: 0.36-0.56). LinkedOmics analysis identified strong positive correlations of ZNF71 with genes such as ZNF470, ZNF256, and ZNF285. Pathway enrichment analyses highlighted associations with herpes simplex virus type 1 infection, the cell cycle, and DNA replication. Negative correlations involved metabolic pathways, peroxisomes, and fatty acid degradation. TIMER2.0 analysis demonstrated positive correlations of high ZNF71 expression with various immune cell types, including CD4+ T cells, B cells, regulatory T cells, monocytes, macrophages, and myeloid dendritic cells.

ZNF71 is significantly upregulated in HCC, correlating with the disease's clinical and pathological stages. It appears to promote HCC progression through mechanisms involving the cell cycle and metabolism and is associated with immune cell infiltration. These findings suggest that ZNF71 could be a novel target for diagnosing and treating HCC.

Hepatocellular carcinoma (HCC) is a prevalent malignancy worldwide, characterized by its high malignancy and poor prognosis. Telomeres, crucial components of eukaryotic chromosomes, have been increasingly recognized for their involvement in tumorigenesis, development, and impact on the prognosis of cancer patients. However, the precise role of telomere-associated genes in HCC remains incompletely elucidated.

The Cancer Genome Atlas (TCGA) database was utilized to download data from 374 HCC and 50 normal liver tissue samples. Differential genes were screened and intersected with 2093 telomere-related genes (TRGs) in GeneCards, resulting in the identification of 704 TRGs exhibiting survival differences. Through univariate Cox regression analysis, multivariate Cox regression analysis, and LASSO regression, a prognostic model consisting of 18 TRGs for HCC risk assessment was developed. The single-cell and spatial transcriptomics were utilized to analyze the expression and distribution of 18 TRGs in HCC. Subsequently, Mendelian randomization (MR) analysis confirmed a causal relationship between ASF1A and alcoholic HCC among the identified 18 TRGs. The expression and functional significance of ASF1A in HCC cell lines were investigated through colony formation assays, Transwell migration assays, and wound healing experiments.

We developed a prognostic risk model for HCC incorporating 18 TRGs. Kaplan-Meier analysis demonstrated that the overall survival (OS) rate of the high-risk group was significantly inferior to that of the low-risk group. Cox regression analysis identified age (HR = 1.017, 95% CI: 1.002-1.032, P = 0.03), stage (HR = 1.389, 95% CI: 1.111-1.737, P = 0.004), and risk score (HR = 5.097, 95% CI: 3.273-7.936, P < 0.001) as three independent risk factors for HCC patients. The five-year receiver operating characteristic curve (ROC) and multivariate Cox regression analysis further validated the accuracy of our model. Time-dependent ROC results revealed that the 1-year, 3-year, and 5-year AUC values were AUC = 0.801, AUC = 0.734, and AUC = 0.690, respectively. The expression and distribution of 18 TRGs in HCC were further validated through single-cell and spatial transcriptomics data. Additionally, immune subtype analysis indicated a significantly lower proportion of C3 and C4 subtypes in the high-risk TRG group compared to the low-risk group. Meanwhile, tumor immune dysfunction and exclusion (TIDE) were significantly higher in the high-risk group than in the low-risk group. Furthermore, we observed differences in IC50 values among nine chemotherapeutic drugs across different TRG risk subtypes which partially confirmed our model's predictive efficacy for immunotherapy. Amongst these eighteen TRGs analyzed by MR analysis, ASF1A was found to be associated with alcoholic HCC pathogenesis. We further confirmed ASF1A was significant overexpression in HCC by Western blotting. We also explored it's the carcinogenic role of ASF1A in HCC via the transwell, wound healing, and clone formation experiments.

In this study, we developed a novel prognostic model comprising 18 TRGs for HCC, which exhibited remarkable accuracy in predicting HCC patients' prognosis. Additionally, through MR analysis, we have successfully established a causal relationship between ASF1A and alcoholic HCC for the first time, which also provided a new theoretical foundation for the management of alcoholic HCC.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, especially in advanced stages where limited treatment options result in poor prognosis. The immunosuppressive tumor immune microenvironment (TIME), characterized by low immune cell infiltration and exhaustion, limits immunotherapy efficacy. To address this, our study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME.

We analyzed CCL3 expression in human HCC samples from The Cancer Genome Atlas database, focusing on its correlation with inflammatory gene signatures and immune cell infiltration. High-dimensional single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence were used to investigate CCL3's effects on macrophage function and T cell activation. The biological impact of CCL3 on macrophages was assessed using co-culture systems, confocal imaging, metabolite detection, and inhibition assays. Preclinical HCC models and ex vivo tumor fragment assays further explored how CCL3 modulates immune responses and enhances immune checkpoint blockade efficacy.

Our study shows that CCL3 is suppressed in the tumor microenvironment and positively correlates with immune infiltration and inflammatory responses. Targeted liver delivery of rAAV-Ccl3 reprograms the immune microenvironment in HCC, promoting immune cell recruitment and tertiary lymphoid structure formation, thus suppressing tumor growth via immune engagement. Through scRNA-seq, flow cytometry, and multiplex immunofluorescence, we found that CCL3 enhances macrophage antigen uptake and activates cytotoxic T cells. In vivo and in vitro experiments confirmed that CCL3 facilitates T cell infiltration and upregulates MHC II expression on macrophages, enhancing antigen presentation. The CCL3-CCR5 pathway also boosts macrophage metabolism, increasing lysosomal activity and antigen uptake, thereby strengthening adaptive immune responses and increasing sensitivity to immune checkpoint blockade therapies in preclinical models.

This study highlights the pivotal role of CCL3 in reshaping the TIME and enhancing antitumor immunity in HCC. By promoting immune cell recruitment and enhancing antigen presentation, CCL3 demonstrates significant potential to improve the efficacy of immunotherapy, particularly in combination with immune checkpoint inhibitors. Targeting CCL3 may help to overcome the immunosuppressive TIME in HCC and improve patient outcomes.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive form of liver cancer, characterized by frequent recurrence and metastasis, which remain significant obstacles to effective treatment. Ammonia accumulates in the tumor microenvironment of HCC due to dysfunction in the urea cycle, but the detailed impact of ammonia on HCC cells remains insufficiently understood.

We exposed HCC cell lines to high concentrations of ammonium chloride to evaluate alterations in proliferation, stemness, and migratory potential. After ammonia removal, changes in cellular behavior were assessed using colony formation, and spheroid assays. Transcriptomic and metabolomic analyses were conducted to investigate ammonia-induced metabolic reprogramming and alterations in gene expression. Additionally, animal models were employed to validate the impact of ammonia on tumor growth and metastasis.

Exposure to high-ammonia conditions transiently suppressed HCC cell proliferation without inducing apoptosis. However, following ammonia removal, cells demonstrated increased proliferation, enhanced spheroid formation, and elevated migratory capacity. Transcriptomic analysis revealed the upregulation of genes associated with cell adhesion, migration, and glycolysis. Concurrently, metabolomic profiling indicated increased lactate production, facilitating the aggressive behavior of HCC cells after ammonia withdrawal. Animal experiments confirmed that high-ammonia exposure accelerated tumor growth and metastasis.

Ammonia exerts a dual effect on HCC progression: it initially suppresses cell growth but later promotes stemness, proliferation, and metastasis through metabolic reprogramming. Targeting ammonia metabolism or glycolysis in the tumor microenvironment may represent a promising therapeutic strategy for mitigating HCC recurrence and metastasis. Future studies utilizing clinical samples are required to validate these findings and identify potential therapeutic strategies targeting ammonia metabolism.

Chloride intracellular channel 6 (CLIC6) is essential for the development of cancer, and it is widely studied for the treatment of various cancers. This study aimed to explore the potential mechanisms of CLIC6 in the treatment of hepatocellular carcinoma (HCC).

Initially, a subcutaneous xenograft model of HCC was established. The model groups were treated with varying levels of CLIC6 recombinant protein. After 21 days, tumor and liver tissues were harvested. Tumor size and weight were measured, and hematoxylin-eosin staining was used to assess histopathological changes in the tumor tissues. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling staining was employed to evaluate apoptosis in tumor tissue cells. Quantitative real-time polymerase chain reaction and Western blot were utilized to analyze cytokine messenger ribonucleic acid ( mRNA) levels in the liver or tumor tissues, and immunohistochemistry was conducted to assess cytokine expression.

CLIC6 significantly inhibits tumor proliferation and enhances apoptosis in tumor tissue cells. CLIC6 markedly reduces the mRNA levels of interleukin (IL)-6, IL-1β, interferon-γ, tumor necrosis factor-α, and IL-17A in liver tissue when increasing transforming growth factor-β and IL-4 mRNA levels. CLIC6 potentially modulates Th cell balance by regulating forkhead box protein P3, GATA-binding protein 3, T-box expressed in T cell, and retinoic acid receptor-related orphan receptor γt (ROR-γt) expression, thereby restraining HCC progression in mice. Moreover, CLIC6 mitigates hepatic oxidative damage via the Janus tyrosine kinase 1/signal transducer and activator of the transcription pathway, attenuates c-Jun N-terminal kinase (JNK) phosphorylation, and modulates apoptosis-related proteins, effectively hindering HCC development.

CLIC6 demonstrates potent antitumor effects in HCC through inhibition of proliferation, promotion of apoptosis, modulation of cytokine levels, regulation of immune cell balance, and attenuation of oxidative stress pathways.

In order to enhance the therapeutic value of curcumin in liver cancer treatment, glycyrrhetinic acid-modified pH-sensitive curcumin liposomes (GA-pH-Lip@Cur) was developed.GA-pH-Lip@Cur was prepared using a thin film dispersion ultrasonication method, and the optimal formulation process was selected through single-factor experiments and a Box-Behnken design-response surface methodology. The liposomes were evaluated for their morphological appearance, particle size, in vitro release at different pH levels, and biocompatibility. The anti-tumor effect of GA-pH-Lip@Cur was assessed using cell viability assays (CCK-8). The in vivo hepatic targeting and anti-liver tumor efficacy of GA-pH-Lip@Cur were evaluated through pharmacokinetic and pharmacological experiments.The results indicated that optimized GA-pH-Lip@Cur exhibited uniform particle size distribution, good stability, pH-sensitive in vitro release with sustained behavior. Compared to conventional liposomes, GA-pH-Lip@Cur showed prolonged average retention time in vivo and significantly increased curcumin distribution in liver tissues, indicating excellent liver targeting. Both in vitro and in vivo evaluations demonstrated the effectiveness of GA-pH-Lip@Cur in inhibiting liver cancer cell proliferation and suppressing liver tumor growth in tumor-bearing mice. In conclusion, GA-pH-Lip@Cur, by leveraging the acidic tumor microenvironment and overexpression of glycyrrhetinic acid receptors in liver cells, encapsulates curcumin to improve its bioavailability, and target its delivery to the liver tumor sites.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.

The 5-methylcytosine (m5C) modification is a crucial epigenetic RNA modification, which is involved in the post-transcriptional regulation of genes. It plays an important role in various biological processes, including cell metabolism, growth, apoptosis, and tumorigenesis. By affecting the proliferation, migration, invasion, and drug sensitivity of tumor cells, m5C methylation modification plays a vital part in the initiation and progression of tumors and is closely associated with the poor tumor prognosis. m5C-related proteins are categorized into three functional groups: m5C methyltransferases (m5C writers), m5C demethylases (m5C erasers), and m5C methyl-binding proteins (m5C readers). This paper introduces several common methodologies for detecting m5C methylation; and reviews the molecular structure and biological functions of m5C readers, including ALYREF, YBX1, YBX2, RAD52, YTHDF2, FMRP, and SRSF2. It further summarizes their roles and regulatory mechanisms in tumors, offering novel targets and insights for tumor treatment.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers, characterized by high morbidity and mortality rates. Recently, immunotherapy has emerged as a crucial treatment modality for HCC, following surgery, locoregional therapies, and targeted therapies. This approach harnesses the body's immune system to target and eliminate cancer cells, potentially resulting in durable antitumor responses. However, acquired resistance and the tumor immunosuppressive microenvironment (TIME) significantly hinder its clinical application. Recently, advancements in nanotechnology, coupled with a deeper understanding of cancer biology and nano-biological interactions, have led to the development of various nanoparticles aimed at enhancing therapeutic efficacy through specific targeting of tumor tissues. These nanoparticles increase the accumulation of immunotherapeutic drugs within the tumor microenvironment, thereby transforming the TIME. In this review, we provide a concise overview of the fundamental principles governing the TIME landscape in HCC and discuss the rationale for and applications of nanoparticles in this context. Additionally, we highlight existing challenges and potential opportunities for the clinical translation of cancer nanomedicines.

Hepatocellular carcinoma (HCC) progression is closely linked to the role of macrophages. This study utilized single-cell RNA sequencing and genomic analysis to explore the characteristic genes of macrophages in HCC and their impact on patient prognosis. We obtained single-cell se-quencing data from seven HCC samples in the GEO database. Through principal component analysis and t-SNE dimensionality reduction, we identified 2,000 highly variable genes and per-formed clustering and annotation of 17 cell clusters, revealing 482 macrophage-related feature genes. A LASSO regression model based on these genes was developed to predict the prognosis of HCC patients, with validation in the TCGA-LIHC cohort demonstrating model accuracy (AUC = 0.78, 0.72, 0.71 for 1-, 3-, and 5-year survival rates, respectively). Additionally, patients in the high-risk group exhibited elevated tumor stemness scores, although no significant differences were observed in microsatellite instability (MSI) and tumor mutational burden (TMB) scores. Immune-related analyses revealed that FCER1G expression was downregulated in HCC and was associated with key pathways such as apoptosis and ferroptosis. Reduced FCER1G expression significantly affected HCC cell proliferation and migration. Our prognostic model provides new insights into precision and immunotherapy for HCC and holds significant implications for future clinical applications.

Hepatocellular carcinoma (HCC) is a common and lethal malignancy of the liver. The aim of this study was to reveal the structural characteristics of FAPP2, evaluate its expression in HepG2 and MHCC97H cells, and explore its potential role and molecular mechanism in the clinical treatment of hepatocellular carcinoma. The role of FAPP2 in these two cell lines was evaluated using cell function tests, such as cell proliferation, migration, and invasion tests. The interaction between FAPP2 and other related signaling pathways was further explored by bioinformatics analysis. The structural analysis of FAPP2 shows that it has specific domains and functional sites, which are closely related to its biological function in the cell. FAPP2 expression in HepG2 cells was significantly higher than that in MHCC97H cells. Functional experiments showed that overexpression of FAPP2 promoted the proliferation and migration of HepG2 cells, but no such effect was seen in MHCC97H cells. Bioinformatics analysis revealed a potential association between FAPP2 and the PI3K/Akt signaling pathway.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150 mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECIST criteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

The mitochondrial solute carrier family 25 (SLC25) is known to play a pivotal role in oncogenesis, yet its specific involvement in hepatocellular carcinoma (HCC) remains poorly elucidated.

In this study, we performed a clustering analysis of HCC patients in the Cancer Genome Atlas database based on the expression levels of SLC25 members, and conducted clinical feature analysis for each patient within the clusters. Subsequently, we developed a prognostic model using a Lasso regression approach with SLC25A19, SLC25A49, and SLC25A51 as features, and generated a risk score for each HCC patient. We then identified SLC25A19 as a potential prognostic marker for HCC through single-cell analysis, and validated this finding using in vitro and in vivo experiments.

Our results revealed significant differences in the expression of most SLC25 family members in HCC patients, enabling the stratification of patients into three clusters, with those in cluster 1 exhibiting the most favorable prognosis and showing a correlation with enhanced immune infiltration. The risk scores derived from the features SLC25A19, SLC25A49, and SLC25A51 effectively predicted the prognosis of HCC patients, with area under the curve (AUC) values exceeding 0.7 in the test group. Single-cell analysis further demonstrated h eightened expression of SLC25A19 in the immune microenvironment of HCC, and in vitro experiments indicated that SLC25A19 may regulate the proliferation, migration, invasion, cycle, and apoptosis of liver cancer cells through the Wnt pathway. In the HepG2 animal model, overexpression of SLC25A19 significantly promotes tumor growth, while knockdown inhibits tumor growth. Analysis of patient tumor tissues shows that SLC25A19 is highly expressed in liver cancer tissues and is associated with CD8+ T cell infiltration.

In conclusion, our comprehensive analysis of the role of SLC25 in HCC unveiled SLC25A19 as a potential regulatory factor in HCC.

Microwave ablation (MWA) is one of the first-line therapy recommended for early-stage hepatocellular carcinoma (HCC). However, the residual tumor, resulting from insufficient ablation, led to recurrence and metastasis of liver cancer. Novel combination strategies are urgently needed to enhance efficiency of MWA.

We detected the expression of XIAP protein after ablation in primary liver cancer patients using immunohistochemistry. Then, we established in vitro and in vivo IMWA models to further detect XIAP expression. We established an in vitro IMWA model by heating HCC cell lines and, at the same time, applied the XIAP inhibitor AZD5582 and verified the proliferation, migration, and pro-apoptotic ability of the XIAP inhibitor on tumor cells using CCK8, colony formation assay, cell scratch assay, and flow cytometry flow. The IMWA model of C57BL/6 and NTG mice were established, and AZD5582 was used in combination to evaluate the inhibitory and pro-apoptotic effects of different treatment regimens on tumor growth and to detect the local immune infiltration of C57BL/6 tumors. Finally, AZD5582 drug toxicity was detected to confirm its feasibility.

XIAP protein expression is significantly increased in recurrent hepatocellular carcinoma tissues of patients who previously received microwave ablation therapy. In vitro experiments showed that the migration and proliferation ability of HCC cells was significantly reduced, and the level of apoptosis was increased after application of the XIAP inhibitor AZD5582. In vivo experiments further confirmed that ablation combined with the application of AZD5582 significantly reduced the proliferation ability of residual hepatocellular carcinoma. Concurrently, in C57 BL/6 mice with AZD5582 application, the level of local CD8+ T-cell infiltration in the tumor was increased, while the level of Foxp3+ regulatory T-cell infiltration was significantly reduced. The low toxicity of AZD5582 was further confirmed through hematological and pathological examinations of vital organs. These results provide new clues for hepatocellular carcinoma treatment, suggesting the potential role of XIAP inhibitors in hepatocellular carcinoma treatment and their impact in immunomodulation.

In this study, we found that the XIAP inhibitor AZD5582 modulates the immune microenvironment and inhibits the progression of post-ablation residual hepatocellular carcinoma.

Liver hepatocellular carcinoma (LIHC) is a highly heterogeneous disease, necessitating the discovery of novel biomarkers to enhance individualized treatment approaches. Recent research has shown the significant involvement of ubiquitin-related genes (UbRGs) in the progression of LIHC. However, the prognostic value of UbRGs in LIHC has not been investigated. In this study, the mRNA expression profiles and clinical data were obtained from public databases of LIHC patients. The least absolute shrinkage and selection operator Cox regression model was employed to construct a multigene signature in the TCGA cohort. Our results showed that a twelve UbRGs signature was developed to categorize patients into two risk groups, with significant differences in expression between LIHC and normal tissues. Patients in the high-risk group exhibited significantly reduced overall survival (OS) and progression-free survival compared to those in the low-risk group. The risk score was identified as an independent predictor for OS in multivariate Cox regression analyses. Receiver operating characteristic curve analysis confirmed the predictive capacity of the signature. Functional analysis revealed enrichment of immune-related pathways and differences in immune status between the two risk groups. The risk score was correlated with 35 transcription factors and 26 eRNA enhancers, and positively associated with tumor mutation burden. Patients in the high-risk group demonstrated decreased sensitivity to targeted and chemotherapeutic drugs than those in the low-risk group. In conclusion, our study identified a twelve UbRGs signature that may serve as a prognostic predictor for LIHC patients and and provide valuable insights for cancer treatment.

Sorafenib is a first-line treatment option for patients with hepatocellular carcinoma (HCC). However, the impact of sorafenib resistance type on patient survival prediction and choice of second-line treatment regimen is unknown.

This study aims to explore the factors predicting resistance in patients with HCC receiving sorafenib, the impact of resistance on survival, and the optimal second-line treatment regimen.

This was a retrospective cohort study.

We recruited all patients with advanced HCC who received first-line sorafenib from January 2019 to January 2023 in two medical centers in China. They were divided into primary and secondary resistance groups according to tumor progression within 3 months. Resistance was the primary outcome of this study. The secondary outcomes were progression-free survival (PFS) and overall survival (OS).

A total of 424 patients met the inclusion criteria, including 165 patients (38.9%) in the primary group and 259 patients (61.1%) in the secondary group. The independent risk factors for primary resistance were alpha-fetoprotein (AFP) > 400 ng/mL and alanine aminotransferase (ALT) > 40 U/L. Patients in the primary group had significantly shorter median OS than those in the secondary group (9.0 months vs 23.0 months, p < 0.001). Compared with tyrosine kinase inhibitor (TKI) monotherapy, the use of TKI plus PD-1 inhibitor combination therapy as second-line treatment conferred a longer median PFS (6.0 vs 10.0 months, p < 0.001) and OS (13.0 vs 22.0 months, p < 0.001).

Sorafenib has a high incidence of primary resistance and short survival in patients who develop primary resistance. AFP and ALT are influential factors in primary resistance, and it is valuable to use these two metrics to guide the use of sorafenib. As second-line therapy, a TKI plus PD-1 inhibitor regimen should be preferentially recommended.

We aim to comprehensively analyze and validate the prognostic efficacy of tetraspanin 4 (TSPAN4) and several other migrasome-related markers in hepatocellular carcinoma (HCC).

The expression, diagnostic, and prognostic efficacy of five migrasome-related genes in HCC were analyzed using several databases. Five pairs of adjacent non-tumor tissues and HCC tissues were used to validate the expression. The prognostic efficacy of TSPAN4 was validated in a HCC cohort. TSPAN4 was knocked down in Huh-7 cells, EdU, and CCK-8, and wound healing assays were conducted to analyze its effects on cell proliferation and migration. In addition, transcriptomic sequencing was used to identify differentially expressed genes.

Compared with those in normal tissues, four genes (TSPAN4, PIGK, NDST1, and CPQ) were elevated in liver hepatocellular carcinoma (LIHC), but not TSPAN7. Of these, only elevated TSPAN4 predicted unfavorable prognosis of HCC patients. The expression and prognostic efficacy of TSPAN4 were further confirmed in a HCC cohort (97 patients); and patients in the TSPAN4high group showed unfavorable overall survival (log-rank P = 0.0055). Functional analysis showed that TSPAN4 knockdown significantly suppressed cell migration, but not cell proliferation. Moreover, TSPAN4 knockdown induced disturbances of the metabolic pathways, mainly pentose and glucuronate interconversions.

TPSAN4 is a promising prognostic and therapeutic target for HCC treatment and may be involved in the metabolic pathways that affect disease progression.

Metastasis is a major cause of fatality in hepatocellular carcinoma (HCC), although the precise mechanisms driving the metastatic process remain incompletely understood. In this study, we have made several important findings. Firstly, we have discovered that elevated activation-induced cytidine deaminase (AID) expression is positively correlated with Jagged 1 (JAG1) levels in clinically metastatic HCC patients. Moreover, we observed that depletion of either AID or JAG1 leads to a reduction in HCC metastasis. Secondly, we have identified AID acts as a transcriptional regulator that regulates JAG1 transcription by interacting with histone acetyltransferase 1 (HAT1) in metastatic HCC cells. Furthermore, our results demonstrate that any domains of AID can cooperate with HAT1 to enhance JAG1 transcription. Importantly, we have determined that the AID/HAT1 complex directly binds to specific regions within the JAG1 gene body, specifically -1.504 kb to -1.104 kb region, thereby influencing the epigenetic state of the JAG1 promoter through modulating histone methylation, histone acetylation, and DNA methylation. Furthermore, we have elucidated that the AID-JAG1/NOTCH-c-FOS axis plays a pivotal role in facilitating HCC metastasis. Consequently, the inhibitory effects of MG149 on both AID and JAG1 significantly mitigate the progression of HCC. This investigation uncovers a heretofore unappreciated function of AID as a transcriptional regulator in the metastasis of HCC, heralding a promising therapeutic approach.

We aimed to explore the comprehensive cancer landscape of Caspase-10 (CASP10). CASP10, a member of the caspase family, is located at the human chromosome locus 2q33-34. Studies have suggested its potential role in the development of certain cancers. To evaluate CASP10 expression in normal and pan-cancer tissues, we integrated data from The Cancer Genome Atlas (TCGA), GEO, Human Protein Atlas (HPA), and UALCAN databases. The diagnostic and prognostic significance of CASP10 was analyzed using Receiver Operating Characteristic (ROC), Cox regression, and Kaplan-Meier analysis. Correlations of CASP10 with clinical parameters were assessed via the Wilcoxon test, Kruskal-Wallis test, and logistic regression analysis. Genomic variations were explored with cBioPortal, GSCALite database, and UALCAN databases. LinkedOmics database was used to detect the function of CASP10 in pan-cancer. Interactions between CASP10 and the Tumor Immune Microenvironment (TIME) were investigated using TISIDB, TIMER2, and TISCH databases. The GSCALite database was utilized to assess the sensitivity of CASP10 to small-molecule drugs. In addition, Western Blotting (WB) was employed to detect the expression of the CASP10 in our clinical Liver Hepatocellular Carcinoma (LIHC) and Stomach Adenocarcinoma (STAD) cohorts. The transcription and protein expression of CASP10 significantly differ across cancer types, marking it as a biomarker for diagnosis and prognosis. Its expression correlated with certain clinical characteristics such as histological types and Alpha-Fetoprotein (AFP) levels. CASP10 gene exhibited a 2% alteration frequency across pan-cancer patients, with significant SNV and CNV profiles, and decreased methylation levels. CASP10 was closely related to the Nuclear Factor-κappa B (NF-κB), TNF, cell cycle, and JAK-STAT signal pathways. CASP10 showed correlation with immune components in the tumor microenvironment, including lymphocytes, immune stimulators, immune inhibitors, MHC molecules, chemokines, receptors, and Cancer-Associated Fibroblasts (CAFs). Importantly, CASP10 could predict the sensitivity of diverse anti-cancer drugs. Finally, WB analysis validated the overexpression of CASP10 in LIHC and STAD tissues. Our comprehensive bioinformatic analysis reveal the function of CASP10 on the diagnosis, prognosis, and progression of diverse cancer types.

Ubiquitin-conjugating enzyme E2 T (UBE2T) is a crucial E2 enzyme in the ubiquitin-proteasome system (UPS), playing a significant role in the ubiquitination of proteins and influencing a wide range of cellular processes, including proliferation, differentiation, apoptosis, invasion, and metabolism. Its overexpression has been implicated in various malignancies, such as lung adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, and ovarian cancer, where it correlates strongly with disease progression. UBE2T facilitates tumorigenesis and malignant behaviors by mediating essential functions such as DNA repair, apoptosis, cell cycle regulation, and the activation of oncogenic signaling pathways. High levels of UBE2T expression are associated with poor survival outcomes, highlighting its potential as a molecular biomarker for cancer prognosis. Increasing evidence suggests that UBE2T acts as an oncogene and could serve as a promising therapeutic target in cancer treatment. This review aims to provide a detailed overview of UBE2T's structure, functions, and molecular mechanisms involved in cancer progression as well as recent developments in UBE2T-targeted inhibitors. Such insights may pave the way for novel strategies in cancer diagnosis and treatment, enhancing our understanding of UBE2T's role in cancer biology and supporting the development of innovative therapeutic approaches.

As the central organ of metabolism, the liver plays a pivotal role in the regulation of the synthesis and metabolism of various nutrients within the body. Ferroptosis, as a newly discovered type of programmed cell death caused by the accumulation of iron-dependent lipid peroxides, is involved in the physiological and pathological processes of a variety of acute and chronic liver diseases. Ferroptosis can accelerate the pathogenetic process of acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, and autoimmune hepatitis; while it can slower disease progression in advanced liver fibrosis and hepatocellular carcinoma. This suggests that targeted regulation of ferroptosis may impact the occurrence and development of various liver diseases. This article reviews the latest research progress of ferroptosis in various liver diseases, including acute liver injury, metabolic associated fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune hepatitis, liver fibrosis and hepatocellular carcinoma. It aims to provide insights for the prevention and treatment of acute and chronic liver diseases through targeting ferroptosis.

In the ongoing quest for new treatments in medicine, traditional Chinese medicine offers unique insights and potential. Recently, studies on the ability of Calculus bovis to inhibit M2-type tumour-associated macrophage polarisation by modulating the Wnt/β-catenin signalling pathway to suppress liver cancer have undoubtedly revealed new benefits and hope for this field of research. The purpose of this article is to comment on this study and explore its strengths and weaknesses, thereby providing ideas for the future treatment of liver cancer.

Hepatocellular carcinoma (HCC) is a highly malignant cancer and lacks effective therapeutic targets. The role of LIM/homeobox protein Lhx3 (LHX3) has been extensively studied in various tumor tissues, where it has been identified as a promoter of tumorigenesis and malignancy. However, the specific functional role and potential mechanism of LHX3 in human HCCs are not clearly clarified. We found that LHX3 was overexpressed in HCC tissues compared to adjacent tissues. Moreover, it was observed that LHX3 promoted the epithelial-mesenchymal transition (EMT) of HCC cells, leading to increased proliferation, migration, and viability, and adhesion ability in vitro. Mechanistically, LHX3 facilitated TCF4 binding to β-catenin, forming a stable LHX3/TCF4/β-catenin complex that activated downstream target genes. Disruption of the β-catenin/TCF4 interaction by Toxoflavin prevented the EMT of HCC cells. Overall, these findings highlight the critical role of LHX3 in the EMT of HCC cells through the β-catenin/TCF4 axis, suggesting the LHX3/β-catenin/TCF4 axis as a potential therapeutic target for HCC treatment.

Hepatocellular carcinoma (HCC) is recognized as a highly malignant tumor. Targeted combination immunotherapy, the initially approved regimen, is compromised by adverse side effects and low response rates during clinical treatment. Traditional Chinese medicine and its derived natural compounds, known for their anticancer effects, offer advantages of low toxicity and cost. In this study, we performed high-throughput phenotypic screening in vitro to identify promising anti-HCC drugs. Among 1,444 bioactive compounds, digoxigenin (DIG) was found to significantly impede HCC cell progression. We validated DIG's therapeutic effects through assays such as cell counting by CCK8, lactate dehydrogenase, and colony formation. Analyses including transmission electron microscopy, western blotting, and immunofluorescence demonstrated that DIG inhibits HCC cell proliferation via autophagy. Network pharmacology and molecular docking studies suggest that DIG targets the PI3K/AKT/mTOR signaling pathway. Comparative treatments of Hep3B and Huh7 cells with DIG or mTOR inhibitors revealed similar inhibitory impacts, indicating that DIG induces autophagy by inhibiting the PI3K/AKT/mTOR pathway. In vivo studies confirmed that DIG halts the growth of subcutaneous xenograft tumors. In conclusion, DIG represents a potential HCC treatment by modulating the PI3K/AKT/mTOR pathway to induce autophagy. This research, via phenotypic screening, accelerates drug discovery and the development of novel therapies targeting the underlying mechanisms of liver cancer.

Plectin, a scaffolding protein overexpressed in tumor cells, plays a significant role in hepatocellular carcinoma (HCC) proliferation, invasion, and migration. However, the use of L-type peptides for targeting plectin is hindered by their limited stability and retention. We designed a D-type plectin-targeting peptide (DPTP) and developed a novel single-photon emission computed tomography (SPECT) probe for HCC imaging. The DPTP targeting ability was evaluated in vitro using flow cytometry and ex vivo fluorescence imaging. 99mTc radiolabeling was performed using tricine and ethylenediamine-N,N'-diacetic acid (EDDA) as coligands after modification with 6-hydrazino nicotinamide (HYNIC) at the N termini of DPTP. The radiochemical purity (RCP), in vitro stability, and binding affinity of the prepared 99mTc-HYNIC-DPTP were analyzed. Tumor uptake, metabolic stability, biodistribution, and pharmacokinetics of 99mTc-HYNIC-DPTP were investigated and compared with those of 99mTc-labeled L-type PTP (99mTc-HYNIC-PTP) in HCC tumor-bearing mice. DPTP could be efficiently radiolabeled with 99mTc using the HYNIC/tricine/EDDA system with a high RCP and good in vitro stability. Compared with the L-type PTP, DPTP exhibited improved targeting ability, and 99mTc-HYNIC-DPTP displayed higher tumor uptake, better metabolic stability, longer blood circulation time, and lower kidney retention, resulting in superior imaging performance and biodistribution in vivo. 99mTc-HYNIC-DPTP has great potential as a novel SPECT probe for diagnosing HCC.