Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations.

The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis.

ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC.

Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.

Tumor-associated macrophages (TAMs) are closely associated with tumor development and patient outcomes due to their plasticity and polarization capacity. Several distinct TAMs have been proposed, but a complete understanding of heterogeneity and differentiation spectrum of macrophage in human primary liver cancer remains elusive.

Deep single-cell RNA sequencing (scRNA-seq) data from 19 primary liver cancer patients were used to profile the transcriptomes of TAMs in liver cancer. Ingenuity pathway analysis (IPA) and in vitro experiments were used to explore possible mechanisms responsible for related signaling pathways altered at the transcriptional level. Finally, we analyzed the relationship between the abundance of the TAMs and the survival outcomes of the 428 patients in the Cancer Genome Atlas (TCGA).

Transcriptional profiles allowed us to identify four distinct TAMs cell subsets based on molecular and functional properties and to reconstruct their developmental trajectory. Specifically, TAM_c4 was preferentially enriched and potentially expanded in the advanced-stage patients or those receiving immune checkpoint blockade therapy (ICT). Gene pathway analysis revealed aberrant TGFB1 activation in TAM_c4, which was experimentally confirmed to drive TAM phenotypic transitions via autophagy signaling. High abundance of TAM_c4 is found to be related to a short survival time and low abundance of CD8+ T cells in primary liver cancers.

This integrated transcriptome compendium and experimental validation offer both mechanistic insights and a resource for understanding TAM heterogeneity in primary liver cancers.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and immunotherapy has demonstrated significant therapeutic benefit in HCC. Indole-3-carbinol (I3C), a naturally occurring ingredient of cruciferous vegetables, significantly inhibits the growth of a wide range of tumors. However, its mechanism of action has not been fully elucidated.

This study aims to verify and explore the immunomodulatory effect of I3C in HCC models, and to investigate the specific role and mechanism by which I3C affects PD-L1 expression through the ubiquitination of NF-κB p105.

In vitro, I3C was treated with HepG2 cells and relevant indicators were analyzed. In vivo, the mouse HCC model was established and the effect of I3C on tumors and immune function was evaluated. Subsequently, the downstream target of I3C was found through target prediction, molecular docking, and molecular dynamics simulation. Finally, combined therapy was used to further investigate the effect of I3C on mouse HCC tumors.

We observed that I3C resulted in decreased programmed cell death ligand 1 (PD-L1) expression in HepG2 cells and increased CD8 T cell infiltration in tissues. Subsequently, target prediction and molecular docking demonstrated that I3C was able to efficiently bind to NF-κB p105. In addition, overexpression of NF-κB p105 upregulated PD-L1 expression and almost completely eliminated the inhibitory effect of I3C. Notably, the combination of I3C and PD-L1 monoclonal antibodies showed synergistic anti-tumor effects in the mouse HCC model.

This study demonstrated that I3C inhibits PD-L1-mediated immune evasion in HCC via suppressing NF-κB p105 ubiquitination. The role of I3C in tumors deserves further investigation and provides the foundation for the future development of novel immunotherapeutic drugs.

We aimed to develop and validate a prediction model to identify HCC in focal liver lesions (FLLs) ≤20 mm among patients at risk for HCC based on clinical and contrast-enhanced ultrasound (CEUS) features.

Between January 2022 and July 2023, 386 patients (mean age 58 ± 11 years; 277 male) at risk for HCC with FLLs ≤20 mm and clinical and preoperative CEUS data from three centers were retrospectively enrolled. Three prediction models based on clinical data (Cli-M), CEUS features (CEUS-M), and combined clinical and CEUS features (Com-M) were constructed using the training cohort (187 patients). Their predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) in the internal and external validation cohorts. All patients were reclassified using the American College of Radiology CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) and combined with the best-performing model (modified LI-RADS).

The AUCs of Com-M were 0.873-0.951 in the training, internal, and external validation cohorts, which were higher than those of Cli-M (0.749-0.795, all P < 0.05) and CEUS-M (0.848-0.899, all P < 0.05). The sensitivity of LR-5 of modified LI-RADS was significantly improved from 83.1 % to 88.9 % (p＜0.001) in the training, internal and external validation cohort while there was no statistical different on its specificity (82.6 %-94.7 % vs 95.7 %-97.6 %., p = 0.162-0.650).

The model based on clinical and CEUS features can help identify HCC in FLLs ≤ 20 mm in high-risk patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with conventional treatments often accompanied by severe side effects. Recently, nanozymes have been extensively employed in cancer therapy due to their enhanced enzymatic activities, stability compared to native enzymes. However, a standalone nanozyme exhibits insufficient targeting capability and fails to specifically localize to the pathological site. In this study, we successfully synthesized a multifunctional iron-based-nanozyme delivery system - Fe3O4-OA-DHCA-PEI-MAN@DSF modified with PEI and MAN by the thermal decomposition method. This mannose-modified nanozyme can specifically target HCC cells via an external magnetic field and mannose-mannose receptor (MRC2) binding. In addition, it exhibits good biocompatibility and pH-dependent drug release characteristics. Within the acidic tumor microenvironment, the iron-based nanozyme initiates intracellular fenton reactions, boosting reactive oxygen species (ROS) production, which ultimately induces apoptosis in HCC cells. Concurrently, the disulfiram small molecule released from the Fe3O4-OA-DHCA-PEI-MAN@DSF nanozyme binds to the FROUNT factor within monocyte-macrophages, thereby inhibiting their response to chemotactic signals emitted by liver cancer cells. This process ultimately suppresses the recruitment of macrophages by HCC cells, reshaping the tumor microenvironment and supporting effective liver cancer treatment. Moreover, this nanozyme system holds potential for MRI-guided targeted chemotherapy combined with chemodynamic therapy, aiming to refine the early diagnosis and precision treatment of hepatic carcinoma, and paving the way for the creation of sophisticated integrated nanoplatforms melding diagnostic and therapeutic functionalities.

Recent findings have demonstrated that Docetaxel (DTX) and Carboplatin (CRP) exhibit significant anticancer and antiproliferative properties in cancer cells. This study aims to explore the effects of DTX on enhancing CRP-induced apoptosis in liver cancer cells and the associated molecular pathways. DTX and CRP cell viability against SMMC-7721 and Bel7402 cells by MTT test. The IC50 values of CRP, DTX, and DTX + CRP for 35 μM, 4.69 μM, and 3.12 μM for SMMC-7721 cells, respectively. The outcomes of the respective fluorescence staining assays displayed that DTX + CRP remarkably enhanced the reactive oxygen species, diminished MMP, and triggered apoptosis in SMMC-7721 cells. DTX + CRP diminished the levels of GSH, CAT, and SOD while enhancing MDA contents in SMMC-7721 cell lines. In SMMC-7721 cells subjected to DTX + CRP, the Bax, Bcl-2, CyC, caspase-3, -8, and -9 expressions were fourfold increased, while Bcl-2 expression was threefold reduced. DTX + CRP enhanced the anticancer efficacy of human liver cancer cells by causing cellular oxidative stress. The hemocompatibility of DTX, CRP, and DTX + CRP was measured at different concentrations. Overall, the results indicate that these DTX + CRP possess potential biomedical uses due to their reduced hemotoxicity, cytotoxicity, and enhanced physiological milieu stability.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, associated with high morbidity and mortality worldwide. Despite advancements in diagnostic methods and systemic treatments, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), the development of drug resistance remains a significant challenge in HCC management. Traditional treatments such as surgical resection and transarterial chemoembolization offer limited efficacy, especially in advanced stages. Although novel therapies like lenvatinib, sorafenib, regorafenib, and ICIs have shown promise, their effectiveness is often hindered by primary and acquired resistance, leading to poor long-term survival outcomes. This review focuses on the molecular mechanisms underlying resistance to targeted therapies and immunotherapies in HCC. Key factors contributing to resistance include alterations in the tumor microenvironment (TME), immune evasion, hypoxia, changes in cellular metabolism, and genetic mutations. Additionally, molecular players such as ferroptosis, autophagy, apoptosis, endoplasmic reticulum stress, ABC transporters, and non-coding RNAs(ncRNAs) are discussed as contributors to drug resistance. Understanding these mechanisms is critical for the development of novel therapeutic strategies aimed at overcoming resistance, improving patient outcomes, and ultimately enhancing survival rates in HCC patients.

Cancer stem cells (CSCs) are strongly associated with the refractory characteristics of Hepatocellular carcinoma (HCC). However, the complex interaction between CSCs and the tumor microenvironment remains incompletely understood. In this study, we identified a novel long non-coding RNA (lncRNA) NEAT1 in cancer-associated fibroblast (CAFs)-derived extracellular vesicles (EVs) that play a critical role in the induction of CSCs and HCC tumorigenesis. NEAT1 was significantly overexpressed in human HCC tissues. Furthermore, high expression of lncRNA NEAT1 in EVs was found to be associated with poor prognosis. Knockdown of NEAT1 in CAFs inhibited invasion, migration, and tumor growth. Mechanistically, NEAT1 promoted cancer cell stemness, including 3D spheroid formation, by facilitating the liquid-liquid phase separation (LLPS) of the transcription factor YAP. Specifically, NEAT1 is directly bound to the intrinsic disordered region in the YAP protein, promoting the formation of LLPS biomolecular condensates. Additionally, a positive correlation between NEAT1 and Nanog was observed in clinical HCC tissues. In conclusion, our findings reveal that NEAT1 promotes HCC carcinogenesis and CSC induction by facilitating the LLPS of the YAP protein.

Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide, and represents a major global health challenge. While surgical resection at early stages offers favorable prognosis with 5-year survival rates exceeding 70%, the clinical reality in China reveals a contrasting scenario, where over 60% of patients present with advanced disease, resulting in a dramatic decline in 5-year survival to below 12.5%. The immunological landscape plays a pivotal role in HCC pathogenesis and progression, comprising two complementary arms: the innate immune system's rapid-response mechanism for immediate tumor surveillance and the adaptive immune system's antigen-specific targeting with immunological memory capabilities. Emerging evidence has highlighted ubiquitination, a sophisticated post-translational modification system, as a critical regulator of immune homeostasis in HCC pathogenesis. This molecular process exerts precise control through three primary mechanisms: (1) Modulation of immune cell activation thresholds via proteasomal degradation of signaling proteins, (2) Orchestrating immune cell differentiation through stability regulation of transcriptional factors, and (3) Maintenance of immune tolerance by dynamic modification of checkpoint regulators. Such multifaceted regulation affects both innate immune recognition pathways (e.g., NF-κB and STING signaling) and adaptive immune effectors (particularly T cell receptor signaling cascades). This comprehensive review establishes a threefold Objective: First, to elucidate the mechanistic interplay between ubiquitination networks and HCC-related immune dysregulation; Second, to systematically analyze how innate immune-associated ubiquitination events drive hepatocarcinogenesis through chronic inflammation modulation; and third, to critically evaluate recent clinical advances combining ubiquitination-targeted therapies (e.g., proteasome inhibitors and E3 ligase modulators) with immunotherapeutic regimens. Our synthesis revealed that strategic manipulation of ubiquitination pathways can potentiate PD-1/PD-L1 blockade efficacy while mitigating therapeutic resistance, particularly through modulation of tumor-associated macrophages and exhausted T cell populations. By integrating fundamental mechanistic insights with translational clinical data, this review provides a conceptual framework for the development of next-generation diagnostic biomarkers and rational therapeutic combinations. The proposed strategy of ubiquitination-immune axis modulation holds significant potential to transform current HCC management paradigms, offering new avenues for precision immunotherapy for this challenging malignancy.

The expression of programmed cell death ligand 1 (PD-L1) enables tumor cells to evade immune surveillance by T-cells. The level of PD-L1 on the cell surface plays a crucial role in the effectiveness of PD-L1-targeted immune checkpoint blockade therapy. Therefore, we utilized the unique trafficking capabilities of scavenger receptors (SRs) to direct PD-L1 to lysosomes for degradation. By employing click chemistry to conjugate the PD-L1 inhibitor BMS-202 with dendritic DNA scaffolds, we created a bifunctional compound, PBL1, which is capable of simultaneously targeting both SRs and PD-L1. PBL1 effectively induces PD-L1 degradation both in vitro and in vivo, significantly reducing the off-target toxicity commonly associated with traditional PD-L1 inhibitors. The efficacy and specificity of PBL1 have been validated in A549 cells and zebrafish models. The development of this SRs-mediated lysosomal degradation strategy offers a promising new approach for cancer immunotherapy, providing a safer and more targeted alternative to existing PD-L1 inhibitors.

The liver is a central metabolic organ, but is also hosting a unique immune microenvironment to sustain homeostasis and proper defense measures against injury threats in healthy individuals. Liver macrophages, mostly represented by the tissue-resident Kupffer cells and bone marrow- or monocyte-derived macrophages, are intricately involved in various aspects of liver homeostasis and disease, including tissue injury, inflammation, fibrogenesis and repair mechanisms.

We review recent findings on defining the liver macrophage landscape and their functions in liver diseases with the aim of highlighting potential targets for therapeutic interventions. A comprehensive literature search in PubMed and Google Scholar was conducted to identify relevant literature up to date.

Liver macrophages orchestrate key homeostatic and pathogenic processes in the liver. Thus, targeting liver macrophages represents an attractive strategy for drug development, e.g. to ameliorate liver inflammation, steatohepatitis or fibrosis. However, translation from fundamental research to therapies remains challenging due to the versatile nature of the liver macrophage compartment. Recent and major technical advances such as single-cell and spatially-resolved omics approaches deepened our understanding of macrophage biology at a molecular level. Yet, further studies are needed to identify suitable, etiology- and stage-dependent strategies for the treatment of liver diseases.

This study aimed to compare the efficacy and safety of atezolizumab plus bevacizumab (T+A) in combination with transarterial chemoembolization (TACE) (T+A+TACE) and T+A for patients with advanced hepatocellular carcinoma (HCC).

From December 2020 to August 2024, 83 patients with advanced HCC who received T+A+TACE treatment or T+A treatment in our hospital were included, and these patients were categorized into TACE+T+A group (n=52) and T+A group (n=31). The clinical outcomes between the two groups were analyzed and compared, and the prognostic factors that affected the efficacy were analyzed.

The median overall survival (OS) and median progression-free survival (PFS) in the T+A+TACE group were significantly longer than those of in the T+A group (OS: 22.8 vs 16.9 months, P = 0.015; PFS: 7.1 vs 4.9 months, P = 0.006). A significantly higher objective response rate (ORR) and disease control rate (DCR) that are based on the modified RECIST were achieved in the T+A+TACE group than those of in the T+A group (ORR: 51.9% vs 6.5%, P < 0.001; DCR: 88.5% vs 54.8%, P < 0.001). No significant differences in adverse events (AEs) were observed between the two groups (P > 0.05). The T+A+TACE treatment was identified as a protective factor for OS and PFS.

TACE further improved the efficacy of T+A treatment for patients with advanced HCC, and it did not increase the incidence of AEs. T+A+TACE treatment is a promising treatment option for patients with advanced HCC.

Neutrophil extracellular traps (NETs), web-like complex structures secreted by neutrophils, have emerged as key players in the modulation of immune responses and the immunopathogenesis of immune disorders. Initially described for their antimicrobial function, NETs now play a part in the fundamental processes of cancer biology, including cancer initiation, metastatic dissemination, and immune evasion strategies. NETs hijack anti-tumor immunity by entrapping circulating cancer cells, fostering the growth of tumors, and reorganizing the tumor microenvironment such that it is pro-malignancy. Emerging evidence emphasizes the role of NETosis coupled with non-coding RNAs-long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)-as key regulators of gene expression and controllers of processes vital for cancer growth, such as immune response and programmed cell death processes like apoptosis, necroptosis, pyroptosis, and ferroptosis. Aberrantly expressed non-coding RNAs have been attributed to immune dysregulation and excessive NET production, promoting tumor growth. NETs are also associated with a myriad of pathological conditions, such as autoimmune disorders, cystic fibrosis, sepsis, and thrombotic disorders. New therapeutic approaches-such as DNase therapy and PAD4 inhibitors-target NET production and their degradation to modify immune function and the efficiency of immunotherapies. Further clarification of the intricate interactions of NETosis, lncRNAs, and miRNAs has the potential to establish new strategies for the suppression of the growth of tumors and preventing immune evasion. This review seeks to elucidate the interactions between NETosis and the regulatory networks involving non-coding RNAs that significantly contribute to the immunopathogenesis of cancer.

This study investigated the role of MDK (Midkine) in hepatocellular carcinoma (HCC) through bioinformatics analysis and experimental validation, focusing on its relationship with tumor immune microenvironment and patient prognosis.

We employed the GEPIA database to analyze MDK expression patterns across cancer types and specifically in HCC versus normal tissues. MDK expression was validated through immunohistochemistry (IHC) in 100 paired HCC and adjacent tissue samples. Survival analyses were conducted using Kaplan-Meier and Cox regression methods. The relationship between MDK expression and immune cell infiltration was investigated using TIMER 2.0 database and verified through IHC staining of immune cell markers.

MDK expression was significantly elevated in HCC tissues compared to adjacent normal tissues. High MDK expression strongly correlated with tumor number, vascular invasion, advanced clinical stage and poor prognosis, serving as an independent prognostic factor. Notably, elevated MDK expression predicted poor outcomes in patients receiving immunotherapy. Database analysis and IHC analysis revealed that MDK expression positively correlated with regulatory T (Treg) cell infiltration while negatively correlating with natural killer (NK) cell presence, suggesting its role in shaping the tumor immune microenvironment.

High MDK expression in HCC correlates with unfavorable patient outcomes and impacts immune cell infiltration. MDK may serve as a novel prognostic biomarker and potential therapeutic target in HCC treatment.

A novel cold-water-soluble polysaccharide (CALP-1-1) was isolated and purified from Citrus aurantium L. Besides determining its in vitro and in vivo anti-tumor activities, its structure was characterised. The results reveal that CALP-1-1 mainly consists of Rha, Ara, Gal, GalA, and GlcA (molar ratio, 1:14.56:19.27:2.27:1.29) with three main linkages. Its average molecular weight was 2.04 × 103 kDa. Moreover, the triple helix structure of CALP-1-1 was proved by Congo-red and circular dichroism (CD). The in vitro experimental results demonstrate that CALP-1-1 significantly inhibited the proliferation of HepG2 cells with typical apoptotic features by inducing cell cycle arrest in the S phase. Furthermore, in vivo anti-tumor experiments suggest that CALP-1-1 could induce H22 solid tumor cells apoptosis and exhibit anti-tumor effects by protecting immune organs and intensifying the secretion of immune cells (macrophages, lymphocytes and NK cells). In conclusion, CALP-1-1 might be a promising component for cancer treatment.

Increasing evidence highlights the pivotal role of RNA methylation and miRNAs in hepatocellular carcinoma (HCC). However, the risk associated with RNA methylation-related miRNAs (RMRMs) in the HCC immune microenvironment remains largely unknown. Here, we predicted the correlation between RMRM risk and immune cell infiltration in HCC using machine learning.

MiRNA sequencing data was used to identify RMRMs. A risk score model of HCC was developed utilizing four RMRMs, including miR-551a, miR-4739, miR-326, and miR-210-3p.

Patients with high-risk scores exhibited poorer prognoses. Single-cell RNA sequencing (scRNA-seq) analysis revealed the high-risk group exhibited increased infiltration levels of several immune cell subtypes, including myeloid-derived suppressor cell (MDSC), macrophage, and T cells. The data integration of scRNA-seq and bulk RNA-seq showed the decreased TIDE score in the high-risk patients and the elevated levels of Macro-secreted phosphoprotein 1 (SPP1), MDSC-meiotic nuclear divisions 1 (MND1), γδ T cells, and Macro-complement C1q C chain (C1QC) predicted adverse prognosis. ScRNA-seq and spatial transcriptomics data integration unveiled the spatial distribution of RMRMs risk scores and their correlation with immune cell subtype localization. Risk model-based clustering of HCC samples revealed that cluster 2, characterized by a higher risk score, correlated with a poorer prognosis and reduced immune and stromal scores. In vitro, the overexpression of miR-4739 in Huh-7 cells significantly induced SPP1+ macrophages, and the culture medium derived from SPP1+ macrophages further promoted the proliferation and migration of Huh-7 cells. Furthermore, miR-4739 reduced m1A methylation by inhibiting tRNA methyltransferase 61A (TRMT61A) expression.

Our study reveals that the RMRM risk model could effectively predict the prognosis of HCC, and SPP1+ macrophages regulated by miR-4739-RNA methylation promote the proliferation and migration of HCC cells. These results highlight the potential of RMRMs in predicting the prognosis of HCC.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.

The study aims to investigate the potential causal effects of lipids on liver cancer risk and to analyze the possible impact of lipid-lowering drug targets on liver cancer.

Genetic variants linked to lipid traits and drug targets were obtained from the Global Lipids Genetics Consortium and DrugBank. Liver cancer data were sourced from FinnGen. Mendelian randomization (MR) was used to assess causal relationships between lipid traits and liver cancer. Functional analyses included protein-protein interaction (PPI), KEGG pathway enrichment, transcription factor (TF) network analysis, and survival analysis. NPC1L1 expression, DNA methylation, and immune infiltration were analyzed using UALCAN, TCGA-LIHC, and TIMER, respectively.

MR analysis showed higher genetically predicted LDL-C levels reduced liver cancer risk (OR = 0.5981, p = 0.034). Drug target MR indicated that NPC1L1 inhibition (OR = 1.0638, p = 0.0311) and elevated PPARɑ levels (OR = 1.1339, p < 0.01) increased liver cancer risk. Functional analysis revealed NPC1L1 was highly expressed in liver cancer tissues due to hypomethylation and linked to immune cell infiltration, indicating its role in immune evasion and tumor progression.

The study demonstrates that elevated LDL-C levels are associated with a reduced risk of liver cancer and NPC1L1 plays a key role in regulating lipid metabolism and influencing immune evasion.

Lenvatinib is one of the molecularly targeted drugs used worldwide in hepatocellular carcinoma (HCC) treatment, but the acquisition of drug resistance is a major problem. The mechanisms that make HCC lenvatinib-resistant (LR) in the tumor microenvironment are largely unknown. Here, we examined the impact of LR HCC cells on tumor-associated macrophages (TAMs) regarding tumor progression and drug resistance, focusing on vascular endothelial growth factor (VEGF) secretion by LR HCC cells.

Hepatocellular carcinoma cells were cultured with lenvatinib to obtain cells with approximately 4-fold lenvatinib resistance. Monocyte-derived macrophages were cultured in the conditioned medium (CM) of LR HCC to induce LR TAMs. Secretion of VEGF by naïve HCC cells, LR HCC cells, TAMs, and LR TAMs was assessed. The macrophage phenotype and VEGFR2 expression in both TAMs were evaluated. Additionally, the effects of inhibiting VEGF secretion in LR HCC cells on the TAM malignant potential were investigated. Tumor-associated macrophages induced by VEGF-inhibited LR HCC were defined as modified LR TAMs.

Secretion of VEGF was elevated in LR HCC. Lenvatinib-resistant TAMs had increased expression of M2-like macrophage markers and increased expression of VEGFR2 compared with naïve HCC-derived TAMs. Lenvatinib-resistant TAM-CM promoted malignant behaviors and lenvatinib resistance in naïve HCC cells and LR HCC cells. However, the modified LR TAMs did not increase M2 polarization markers or decreased VEGFR2 expression. The elevated VEGF secretion in LR TAMs was not seen in modified LR TAMs.

Increased VEGF secretion from LR HCC promoted malignant behaviors and lenvatinib resistance through LR TAMs in the tumor microenvironment.

Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.

Cytotoxic T lymphocytes (CTLs) play a crucial role in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has indicated that junctional adhesion molecule-like protein (JAML) enhances the antitumor activity of CD8+ T cells. Our study investigates the role of JAML+ CD8+ T cells in HCC.

We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cells differentiation and JAML expression in CD8+ T cells infiltrating HCC. Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+ (LDHA+) CD4+ T cells and JAML+ CD8+ T cells. Subsequently, we evaluated the therapeutic effects of an agonistic anti-JAML antibody, both alone and combined with immunotherapy. Finally, RNA sequencing was conducted to identify potential regulatory mechanisms.

Immunotherapy significantly increased the percentage of CD8+ T cells infiltrating HCC and induced histone modifications, such as H3K18 lactylation (H3K18la) in CD4+ T cells. Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. LDHA, an enzyme that converts pyruvate to lactate, plays a key role in this process. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients who responded to immunotherapy. Moreover, high JAML expression in CD8+ T cells was associated with a more favorable prognosis. In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the effects of anti-programmed cell death protein ligand-1 antibody (αPD-L1)-mediated immunotherapy. Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.

Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with limited treatment options for advanced stages. Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to the harsh tumor microenvironment (TME) and evade immune surveillance. This review involves the role of metabolic reprogramming in HCC, focusing on the dysregulation of glucose, lipid, and amino acid metabolism, and its impact on immune evasion. Key metabolic pathways, such as the Warburg effect, fatty acid synthesis, and glutaminolysis, are discussed, along with their influence on tumor-associated macrophages (TAMs) and immune cell function. Targeting these metabolic alterations presents a promising therapeutic approach to enhance immunotherapy efficacy and improve HCC patient outcomes.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and its incidence and mortality have increased year by year. HCC research has increasingly focused on understanding its pathogenesis and developing treatments.The Wnt signaling pathway, a complex and evolutionarily conserved signal transduction system, has been extensively studied in the genesis and treatment of several malignant tumors. Recent investigations suggest that the pathogenesis of HCC may be significantly influenced by dysregulated Wnt/β-catenin signaling. This article aimed to examine the pathway that controls Wnt signaling in HCC and its mechanisms. In addition, we highlighted the role of this pathway in HCC etiology and targeted treatment.

Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor's immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for 90% of all cases. Currently, early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection, B-ultrasound, and computed tomography scanning; however, their specificity and sensitivity are suboptimal. Despite significant advancements in HCC biomarker detection, the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis. Therefore, it is crucial to explore more sensitive HCC biomarkers for improved diagnosis, monitoring, and management of the disease. Long non-coding RNA (lncRNA) serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity. Moreover, investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC. We searched the PubMed database for literature, comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells. Furthermore, we prospectively summarize its potential implications in diagnosing and treating HCC.

Hepatocellular carcinoma (HCC) represents a highly aggressive malignancy with significant global health implications. The proteasome subunit beta type-8 (PSMB8) gene, known for its association with hepatitis B virus susceptibility, has emerged as a potential regulator of tumor progression. However, its functional role and clinical significance in HCC remain poorly characterized.

We conducted a comprehensive multi-omics analysis to elucidate the role of PSMB8 in HCC. PSMB8 expression profiles were derived from The Cancer Genome Atlas and validated using the GSE76427 dataset. Prognostic significance was assessed through Kaplan-Meier survival analysis. Then, we systematically evaluated the relationships between PSMB8 expression and clinicopathological features, somatic mutations, immune cell infiltration, immune regulatory genes, and immune checkpoint responses. Single-cell RNA sequencing data from the Tumor Immune Single-cell Hub database were analyzed to determine cell type-specific PSMB8 expression. Tissue-level validation was performed using multiplex immunofluorescence staining on HCC tissue microarrays.

PSMB8 demonstrated significant overexpression in HCC tissues and exhibited strong prognostic value. Single-cell analysis revealed predominant PSMB8 expression in T and B cell populations. Notably, PSMB8 expression showed significant positive correlations with immune checkpoint molecules PD-L1/CD274 and CD27. Functional enrichment analysis implicated PSMB8 in multiple oncogenic pathways, particularly proteasome-related processes.

Our findings position PSMB8 as a promising prognostic biomarker and potential therapeutic target in HCC. The observed associations with immune checkpoint molecules and proteasomal pathways suggest its potential role in modulating tumor immunity and protein homeostasis, warranting further investigation into its mechanistic contributions to HCC progression.

To clarify computed tomography (CT) imaging features of high fibroblast activation protein (FAP) expression in hepatocellular carcinoma (HCC) and to investigate their correlation to histological characteristics and prognosis.

This retrospective multicenter study evaluated patients with HCC who underwent liver resection between August 2013 and June 2023. Histological staining for FAP was performed, and patients were classified into low and high-FAP expression groups. A predictive model was developed and validated to identify FAP expression levels among CT imaging features. Moreover, CT imaging-related histological characteristics were evaluated. With the predictive model, patients in training cohort were stratified into predicted low and high-FAP expression groups. Overall survival (OS) and recurrence-free survival (RFS) were compared accordingly. Besides, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were performed, and OS and RFS between the two groups were also compared.

In total, 1197 patients were included (high-FAP HCCs, n=267). Delayed central enhancement (OR: 15.196, 95% CI: 8.996-25.670, P<0.001) and dilated vasculature (OR: 7.455, 95% CI: 4.928-11.277, P<0.001) independently predicted high-FAP expression (AUCs: 0.779, training; 0.766, external validation). Based on these two CT imaging features, intratumoral fibrosis (ITF) and vessel-encapsulating tumor cluster (VETC) pattern were determined. Compared to low-FAP HCCs, high-FAP HCCs were more frequently with high ITF grade (54.7% vs. 22.4%; P<0.001) and VETC pattern (52.1% vs. 22.6%; P<0.001). Patients were divided into predicted low (n=564) and high (n=262) FAP expression groups. The predicted low-FAP group had significantly better or favorable trend toward improved OS and RFS than predicted high-FAP group before (P<0.001, OS and RFS), and after PSM (P=0.009, OS; P=0.005, RFS) and IPTW (P=0.019, OS; P=0.077, RFS).

Delayed central enhancement and dilated vasculature are independent factors of high-FAP expression in HCC. Noninvasive identifying FAP expression may offer potential prognostic and therapeutic insights.

Liver hepatocellular carcinoma (LIHC) strongly contributes to global cancer mortality, highlighting the need for a deeper understanding of its molecular mechanisms to enhance patient prognosis and treatment approaches. We aimed to investigate the differential expression of immunogenic cell death-related genes (ICDRGs) and cellular senescence-related genes (CSRGs) in LIHC and their effects on patient prognosis. We combined the GSE25097, GSE46408, and GSE121248 datasets by eliminating batch effects and standardizing the data. After processing, 16 genes were identified as ICDR&CSR differentially expressed genes (ICDR&CSRDEGs), including UBE2T, HJURP, PTTG1, CENPA, and FOXM1. Gene set enrichment analysis indicated a strong enrichment of these genes in pre-Notch expression and processing. Gene set variation analysis revealed 20 pathways with significant differences between the LIHC and control groups. Mutation analysis identified TP53 as the most commonly mutated gene in LIHC samples. A prognostic risk model integrating 12 ICDR&CSRDEGs was developed, showing high precision at 1 year but diminished accuracy at 2 and 3 years. Our constructed prognostic risk model provides valuable insights for predicting patient outcomes and may guide future therapeutic interventions targeting these specific genes. Further research is needed to explore the mechanistic roles of these genes in LIHC progression and treatment response.

Liver cancer is one of the major causes of cancer-related death in the world. As a breakthrough therapy, immunotherapy had significantly improved the prognosis of patients. However, the current research status and research hotspots in the field of liver cancer immunotherapy still lack systematic review. Based on the bibliometric analysis of highly cited papers, this study intended to reveal the current research status, research hotspots and future research trends in this field.

The purpose of this study was to analyze the national/regional contributions, authors and institutions cooperation network, keywords clustering and keywords burst analysis of highly cited papers on liver cancer immunotherapy through bibliometrics, so as to clarify the research frontier and development direction, and provide objective data support for future research direction and clinical practice.

The highly cited papers on liver cancer immunotherapy from the Web of Science core collection up to February 23, 2025 were retrieved, and 232 studies were included. CiteSpace was used to build a knowledge map, analyze the distribution of years, countries, authors, institutions and cooperation networks, and identify research hotspots and emerging trends through keyword clustering and burst detection.

The number of highly cited papers continued to increase from 2014 and reached a peak in 2022. China and the United States had the highest number of publications and the centrality of cooperation networks. The author with the highest number of papers was Llovet, Josep M, whose research direction mainly focused on immune checkpoint inhibitor combination therapy and molecular typing. The author with the highest cooperation network centrality was Duda, Dan G, whose research team focused on tumor microenvironment regulation. Harvard University and the University of Barcelona played an important central role in the institutional collaboration. Keywords analysis showed that immune checkpoint inhibitors, tumor microenvironment and combination therapy were the core of liver cancer immunotherapy. Burst keywords such as cell lung cancer, pembrolizumab, advanced melanoma, blockade, lymphocytes, etc. had revealed the research frontier of liver cancer immunotherapy research.

The research on liver cancer immunotherapy had made multi-dimensional progress, with China and the United States leading the global cooperation. The main research directions were the combination strategy of immunization, the regulation of tumor microenvironment and the exploration of novel targets. In the future, it is necessary to optimize treatment resistance solutions, integrate interdisciplinary resources, and promote the development of precision and personalized treatment.

Hepatocellular carcinoma (HCC) is the dominant type of liver cancer and is associated with a high mortality rate. However, HCC lacks biomarkers for diagnosis and immune therapy response. Tumor-derived exosomes (TDEs) carcinogen-specific molecules have been used for screening multiple biomarkers. This study aimed to identify new biomarkers for the diagnosis of HCC and response to immune checkpoint blockade (ICB) therapy.

Analysis of differentially expressed genes (DEGs) in HCC and normal tissues was integrated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ExoCarta datasets. The expression of CCT3 was validated in samples from patients with HCC using quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC) techniques.

Exosomal CCT3 was identified as a potential biomarker with significant impact. The expression of CCT3 in different tumor stages and normal tissues adjacent to the tumors (NATs) was validated using qPCR, western blotting, and IHC. CCT3 expression significantly increased the number of activated natural killer cells in HCC, as confirmed by qPCR and IHC. CCT3 expression significantly increases the expression of immune checkpoints in HCC. HCC-derived exosomes significantly increase the enrichment of CCT3.

Exosomal CCT3 is a biomarker for diagnosis and ICB therapy of HCC via MYC pathway activation and immune infiltration.

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of hepatocellular carcinoma (HCC), especially those with unresectable advanced stages. The field has progressed rapidly, and the research hotspots have significantly changed compared to previous years. The study aims to comprehensively review and analyze the development history, knowledge structure, current research focus, and emerging trends in ICIs for HCC.

Reviews and articles published in English from The Web of Science Core Collection (WoSCC) database from 2014 to 2024 were systemically retrieved. Citespace, VOSviewer, and Bibliometrix R package were used for further bibliometric analysis and visualization for countries, institutions, authors, references, and keywords.

2,941 records were included for analysis. The literature on ICIs for HCC has continued to grow steadily over the past decade. Three major research centers have emerged: North America, Europe, and East Asia. The Chinese institution has the highest publication volume, but Kudo Masatoshi from Japan has the highest number of publications. At the same time, Richard S. Finn from the United States leads in citations and co-citations. The most prolific journal is "Cancers". The clustering and Timeline view of critical literature and keywords indicated that research on ICIs for HCC is rapidly advancing toward a more evidence-based, personalized, and multimodal approach. Immune evasion mechanisms, predictive biomarkers, and high-quality clinical trials focusing on Novel combination, conversion, and perioperative therapies, including ICIs, are emerging hotspots.

This study highlights the groundbreaking advancements of ICIs in treating HCC and shows a trend rapidly advancing towards a more evidence-based, personalized, and multimodal approach. The study updated the current understanding of ICIs in hepatocellular carcinoma and identified vital future directions for research, such as the exploration of mechanisms of immune evasion, developing predictive biomarkers, and combining therapy strategies.

Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe3+ to free Fe2+, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

To investigate the prognostic value of GPN1 in cancer and its role in the migration of hepatocellular carcinoma (HCC or LIHC) cells, we used several databases to assess GPN1 expression levels and effects in human tumors. Furthermore, experiments were conducted to verify changes in GPN1 expression in HCC cell lines and explore its biological function. We found that GPN1 gene and protein expression were significantly increased in several tumor tissues. Higher GPN1 expression was associated with unfavorable overall survival. Additionally, there was a strong association between GPN1 expression and several clinicopathological features, according to multivariate Cox regression analysis. Moreover, GPN1 gene mutation and methylation were present in some tumors. A relationship was also found between GPN1 expression and immune infiltration. Notably, immune checkpoint analysis showed that GPN1 expression was correlated with PD-1/PDL-1 and CTLA-4, suggesting it may serve as a biomarker for predicting immune subtypes and response to immunotherapy in HCC. Enrichment analysis in HCC indicated that GPN1 is primarily involved in RNA metabolism. Additionally, drug sensitivity analysis revealed that GPN1 appeared to be responsive to 16 drugs. Finally, GPN1 upregulation was confirmed to promote the migration of HCC cells. This study provides a comprehensive overview of GPN1 in human cancer and demonstrates that GPN1 contributes to the migration of HCC cells, potentially serving as a prognostic and immunotherapy biomarker.

Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC.

Bioinformatics was used to investigate TMEM115 mRNA expression and immune infiltration score. Through multiplex immunohistochemistry analysis, we assessed its protein expression and association with HCC patient clinical features, prognosis and immune cell infiltration in HCC. Through in vitro and in vivo experiments, we evaluated the biological functions of TMEM115 in HCC cells and its impact on the immune microenvironment.

TMEM115 mRNA and protein levels were significantly higher in HCC tissues compared to paracancerous liver tissues. Its protein expression correlated with clinical characteristics and overall survival in HCC patients. In HCC tissues, higher TMEM115 protein expression corresponded to lower proportions of CD66b+ neutrophils and CD8+ T cells and a higher proportion of CD4+ T cells. Furthermore, patients with low TMEM115 expression displayed higher programmed cell death ligand-1 and lower lymphocyte activation gene 3 protein expression. Functionally, TMEM115 knockdown inhibited the proliferation, migration and invasion of HCC cells. In orthotopic models, TMEM115 knockdown inhibited the growth of HCC and affected the infiltration of immune cells.

Our findings show TMEM115 as a promising prognostic indicator for HCC and hold promise in predicting responses to immune therapy, emphasising its potential clinical relevance and intricate involvement in the immune microenvironment of HCC.

The complex pathogenesis of hepatocellular carcinoma (HCC) limits the effectiveness of current therapies. Through RNA sequencing of cancerous and adjacent non-cancerous tissues from six HCC patients, we identified a significant upregulation of MCM2-7 genes, which encode proteins that form the MCM complex, a DNA helicase involved in DNA replication and cell cycle progression. We focused on MCM2, MCM3, and MCM7, and observed that knockdown of these proteins inhibited HCC cell proliferation. Further analysis revealed a critical regulatory axis involving EZH2, the MCM complex, and hTERT. EZH2 was found to be highly correlated with MCM complex gene expression and directly bound to the MCM gene promoters, regulating their expression. This EZH2/MCM complex/hTERT axis may play a key role in suppressing cellular senescence, thereby promoting HCC progression. Knocking down MCM complex genes reduced hTERT expression, inducing HCC cell senescence and enhancing the therapeutic efficacy of sorafenib. These findings suggest that the EZH2/MCM complex/hTERT axis could serve as a novel therapeutic target for HCC.

Hepatocellular carcinoma remains a significant threat to human health. Recent studies have found that the intake of cellular cholesterol contributes to the development and progression of hepatocellular carcinoma, although the exact mechanisms remain unclear. Our analysis of transcriptomic and proteomic databases has identified increased mRNA and protein expression levels of NPC1, a cholesterol intracellular transporter protein, in hepatocellular carcinoma tissues. This increase is significantly associated with a worse prognosis for patients. To corroborate these findings, we performed immunohistochemical staining of NPC1 on liver tissue samples from patients, revealing significantly higher expression levels of NPC1 in hepatocellular carcinoma tissues compared to normal tissues. Subsequent investigations have revealed that NPC1 expression does not significantly influence the proliferation of hepatocellular carcinoma cells in vitro. However, it has a substantial inhibitory effect on the progression of hepatocellular carcinoma tumors when observed in vivo. Utilizing flow cytometry to monitor cellular changes within the tumor microenvironment has led us to discover that NPC1 plays a crucial role in the regulation of neutrophil recruitment within the tumor. Using further neutrophil depletion experiments, we determined that the role of NPC1 in advancing hepatocellular carcinoma progression truly relies on neutrophils. These observations are further reinforced by a comprehensive analysis of clinical databases alongside immunohistochemistry findings. In conclusion, our research suggests that NPC1's overexpression could contribute to hepatocellular carcinoma progression by promoting neutrophil recruitment, positioning NPC1 as a promising new biomarker and therapeutic target for hepatocellular carcinoma.