Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, characterised by its complex pathogenesis and poor therapeutic outcomes. Despite recent advances in targeted molecular therapies, immune checkpoint inhibitors (ICIs), radiotherapy and conventional chemotherapy, the 5-year survival rate for this neoplasm remains dismally low. The progress in nanotechnology has revolutionised cancer treatment in recent years. These advances provide unprecedented opportunities to overcome the current limitations of different therapeutic modalities. This review provides a comprehensive analysis of how nanotechnology interfaces with the tumour immune microenvironment (TIME) in HCC and can present a new frontier in therapeutic interventions for HCC. We critically overview the latest developments in nanoparticle-based delivery systems for various drugs and also other antitumor agents like thermal therapy and radiotherapy. We also highlight the unique ability of nanoparticles to modulate the immunosuppressive tumour microenvironment (TME) and enhance therapeutic efficacy. Furthermore, we analyse emerging strategies that exploit nanoformulations to overcome biological barriers and enhance drug bioavailability in HCC treatment.

Coagulation is intensively related to various tumors, which affects their progression and prognosis. However, research on the impact of coagulation-associated genes (CAGs) on hepatocellular carcinoma (HCC) occurrence, prognosis, and immune microenvironment is limited. Consequently, our research aims to uncover how CAGs affect the prognosis and immune microenvironments of HCC. We integrated gene expression data and clinical information from three datasets (GSE14520, GSE76427, and TCGA-LIHC). 281 CAGs were obtained from the coagulation-related pathway (hsa04610). We obtained three CAG patterns through a consensus clustering algorithm. Afterward, differential analyses of prognosis, biological processes, immune infiltration, and functional and pathway enrichment were conducted on the three CAG patterns. We intersected CAGs with differentially expressed genes in GSE76427 and then conducted Cox regression analysis to obtain the prognostic genes in HCC. Glycerol-3-phosphate dehydrogenase 2 (GPD2) was selected for further analyses. TCGA-LIHC samples with different GPD2 expression levels were analyzed for prognosis, DNA methylation, immune infiltration, and drug sensitivity. The expression level of GPD2 was verified through quantitative real-time PCR (qPCR) and immunohistochemistry. The wound-healing and Transwell assays were used to analyze the tumor cell migration and the Matrigel invasion and apoptosis assays were performed to determine cell invasion and apoptosis. Three CAG patterns were obtained through an unsupervised consensus clustering algorithm. CAGclusterA held the best prognosis compared to the other two clusters. The CAGclusterC was characterized by poor prognosis and abundant immune cell infiltration. The TCGA-LIHC dataset, as an internal validation, also yielded similar subtype classifications. Afterward, we identified the GPD2 gene, which significantly affected the prognosis of HCC and was positively correlated with the tumor progression. The upregulation of GPD2 expression was closely related to tumorigenic signatures and immune escape. The qPCR confirmed the upregulation of GPD2 expression in HCC tumor cell lines, compared to normal liver cell lines. Immunohistochemical staining confirmed the high expression of GPD2 in HCC tumor tissues compared to normal tissues. Regulating the expression level of GPD2 can inhibit the proliferation, migration, invasion, and induce apoptosis of HCC cells. Our study comprehensively elucidated the coagulation characteristics in HCC and identified a promising oncogenic gene GPD2. Exploring targeted strategies based on coagulation-related characteristics and biomarkers may shed light on HCC treatment.

Hepatocellular carcinoma (HCC) is a prevalent liver malignancy. This study examined the roles of transforming growth factor beta (TGF-β) and cytochrome b5 domain containing 2 (CYB5D2) in HCC etiology and their prognostic biomarker potential.

Key modules and prognostic genes were identified by analyzing the GSE101685 dataset by weighted gene co-expression network analysis (WGCNA) and Least absolute shrinkage and selection operator (LASSO) Cox regression. The expression levels of CYB5D2 and TGF-β in HCC cell lines were quantified using Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) assays. Effects of CYB5D2 overexpression on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) marker regulation were assessed in vitro, while in vivo tumorigenicity was evaluated using a xenograft model of HCC in nude mice.

In this study, WGCNA identified the turquoise module as significantly associated with HCC, containing 452 DEGs. LASSO Cox regression analysis revealed 9 key prognostic genes, with CYB5D2 being underexpressed in HCC cells and tissues. TGF-β was negatively correlated with CYB5D2 expression, resulting in poor patient prognosis. Functional assays demonstrated that CYB5D2 overexpression inhibited proliferation, migration, and invasion of HCC cell lines, and altered EMT marker expression. Furthermore, the addition of TGF-β partially reversed the suppressive effects caused by CYB5D2 overexpression. In vivo, CYB5D2 overexpression significantly reduced tumor growth, indicating its potential as a therapeutic target for HCC.

The tumor suppressor function of CYB5D2 in HCC and its interaction with TGF-β offered fresh information on the molecular pathophysiology of HCC and possible treatment avenues.

Accumulating studies have highlighted the biological significance of immunogenic cell death (ICD) in cancer immunity. However, the influence of ICD on tumor microenvironment (TME) formation and immune response in Hepatocellular carcinoma (HCC) remains largely unexplored. In this study, we systematically analyzed the mRNA profiles of ICD-related genes in 1847 HCC patients and identified three molecular subtypes with significantly different immune features and prognostic stratification. A reliable risk model named ICD score was constructed via machine learning algorithms to assess the immunological status, therapeutic responses, and clinical outcomes of individual HCC patients. High ICD score indicated an immune-excluded TME phenotype, with lower anticancer immunity and shorter survival time. In contrast, low ICD score corresponded to abundant immune cell infiltration, high sensitivity to immunotherapy and a positive prognosis, indicating an "immune-hot" phenotype. Pan-cancer analysis further validated a negative association between ICD score and the immune cell infiltration levels. In conclusion, our findings revealed that the ICD score could serve as a robust prognostic biomarker to predict the benefits of immunotherapy and optimize the clinical decision-making of HCC patients.

Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis. Several risk factors, such as pre-existing autoimmune and liver diseases, the type of immunotherapy, and combination regimens, play a role in immune-related hepatotoxicity (irH), although reliable predictive markers or models are still lacking. The severity of irH ranges from mild to severe cases, up to, in rare instances, acute liver failure. Management strategies require regular monitoring for early diagnosis and interventions, encompassing strict monitoring for mild cases to the permanent suspension of immunotherapy for severe forms. Corticosteroids are the backbone of treatment in moderate and high-grade damage, alone or in combination with additional immunosuppressive drugs for resistant or refractory cases. Given the relatively low number of events and the lack of dedicated prospective studies, much uncertainty remains about the optimal management of irH, especially in the most severe cases. This review presents the main features of irH, focusing on injury patterns and mechanisms, and provides an overview of the management landscape, from standard care to the latest evidence.

The prognosis of cancers is strongly connected with nitrogen metabolism (NM), which plays a critical role in the microenvironment and growth of tumors. It is unsubstantiated, however, how important NM-related genes are for the prognosis of hepatocellular carcinoma (HCC).

Using publicly available data, we examined potential mechanisms of NM-related genes in HCC, created a predictive model, and assessed immune infiltration and medication sensitivity.

A prognostic model, which included 12 NM genes (COLQ, GNE, ISCU, MSRA, SARS2, SPHK1, CBS, GOT2, CHST1, EXTL2, GCLM, YARS1), was constructed based on regression analysis. The robustness of the model was validated using multiple methods. The high-risk (HR) and low-risk (LR) groups had varying degrees of immune infiltration, according to an immunology-related study. Of these, B cells and Type_II_IFN_Response were greatly infiltrated in the LR group, whereas aCDs, Macrophages, and Treg were heavily infiltrated in the HR group (p < 0.05). Because of higher immunophenoscore, the low-risk group could benefit from immunotherapy more. Drug sensitivity predictions indicated that people with high CBS expression and low GOT2 and ISCU expression may benefit more from treatment with SCH-772984, Pimasertib, Cobimetinib (isomer1), TAK-733, LY-3214996, ARRY-162, Cladribine, Fludarabine, and Hydroxyurea.

This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening.

Tripterygium hypoglaucum (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3-O-acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of IκBα, NF-κB p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the RORγt/Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis.

The immune microenvironment (IME) plays a crucial role in the progression of hepatocellular carcinoma (HCC). In HCC, the IME is often compromised by hepatitis B virus (HBV) infection, chronic inflammation, and fibrosis. Both antiviral therapy (AVT) and the alleviation of inflammation and fibrosis (AIF) have been shown to improve prognosis. However, the relationship among the IME of HCC, AVT, and AIF remains unclear.

A total of 140 and 110 primary HBV-related HCC patients were enrolled as training and validation sets, respectively, to establish a HCC-immune microenvironment score (H-IME score). Immunohistochemistry was performed to assess the number of granzyme B+ (GrB+) and Foxp3+ cells, as well as the expression of CTLA-4, PD-1, LAG3, TIGIT, TIM3, and VISTA. Another cohort consisting of 114 recurrent HBV-related HCC patients with paired primary and recurrent tissues was used to study the relationship among the IME of HCC, AVT, and AIF.

The H-IME score, including GrB, Foxp3, CTLA-4, PD-1, LAG3, and TIGIT, was established to evaluate the IME. A higher H-IME score indicates stronger immunosuppressive activities. Both AVT and AIF were found to inhibit immunosuppressive activities in the IME. Compared to primary tumors, the H-IME scores of recurrent tumors in the effective AVT group (e-AVT, classified by HBV DNA) with AIF decreased, while the scores increased in the non-AVT group without AIF.

The IME of HCC is closely related to AVT and AIF. e-AVT can enhance anti-tumor activities in the IME by alleviating inflammation and fibrosis.

Recent research has shown that Doublecortin-like kinase 1 (DCLK1) is overexpressed in different types of cancer. It has recently been described as a cancer stem cells (CSCs) marker, is associated with carcinogenesis, and positively correlates with infiltration of multiple immune cell types in some cancers. However, studies focused on assessing DCLK1 expression in HCC are limited, and the role of DCLK1 in HCC tumor immunity remains to be determined. In this study, we used a modified model of the resistant hepatocyte (MRHM) to evaluate DCLK1 expression in HCC. Furthermore, DCLK1 expression in HCC was analyzed using TIMER 2.0, UALCAN, GEPIA, GEO, and HPA web-based tools. Correlations between DCLK1 expression and clinicopathological factors in patients were analyzed using the UALCAN web-based tool. Finally, correlations between DCLK1 and immune infiltrates were investigated using the TIMER 2.0 and TISIDB web-based tools. The results showed that DCLK1 is significantly overexpressed during progression of the HCC carcinogenic process in the MRHM. DCLK1 is overexpressed in HCC according to multiple publics web-based tools, and its overexpression is associated with cancer stage. Furthermore, DCLK1 expression was correlated with infiltration levels of multiple immune cells, immunomodulatory factors, immunoinhibitors, MHC molecules, chemokines, receptors, and immune cell-specific markers. These results suggest that DCLK1 is a potential prognostic biomarker that determines cancer progression and correlates with immune cell infiltration in HCC.

Despite advancements in breast cancer treatment, therapeutic resistance, and tumor recurrence continue to pose formidable challenges. Therefore, a deep knowledge of the intricate interplay between the tumor and the immune system is necessary. In the pursuit of combating breast cancer, the awakening of antitumor immunity has been proposed as a compelling avenue. Tumor stroma in breast cancers contains multiple stromal and immune cells that impact the resistance to therapy and also the expansion of malignant cells. Activating or repressing these stromal and immune cells, as well as their secretions can be proposed for exhausting resistance mechanisms and repressing tumor growth. NK cells and T lymphocytes are the prominent components of breast tumor immunity that can be triggered by adjuvants for eradicating malignant cells. However, stromal cells like endothelial and fibroblast cells, as well as some immune suppressive cells, consisting of premature myeloid cells, and some subsets of macrophages and CD4+ T lymphocytes, can dampen antitumor immunity in favor of breast tumor growth and therapy resistance. This review article aims to research the prospect of harnessing the power of drugs, adjuvants, and nanoparticles in awakening the immune reactions against breast malignant cells. By investigating the immunomodulatory properties of pharmacological agents and the synergistic effects of adjuvants, this review seeks to uncover the mechanisms through which antitumor immunity can be triggered. Moreover, the current review delineates the challenges and opportunities in the translational journey from bench to bedside.

Both Ku80 and Ku70 are promising drug targets for hepatocellular carcinoma (HCC) and crucial for immune regulation. However, their correlation with HCC immune signatures has not yet been investigated. Therefore, we aimed to investigate the relationship between Ku80, Ku70, and immune signatures in HCC and validate their significance in cytotoxic lymphocyte (CTL) immunotherapy.

Analyses of Ku70, Ku80, and immune signatures in public datasets was performed using R software, an online Kaplan-Meier plotter, g:Profiler, GeneTrail, and Metascape. Uniform manifold approximation and projection, correlation chord diagrams, Pearson's correlation tests, and Spearman correlation tests were used to describe various correlation levels. HCC mRNA sequencing data (n=373 tumor samples and n=50 para-tumor samples) were drawn from The Cancer Genome Atlas (TCGA) public database. Immunofluorescent staining was used to validate Ku70/Ku80 and CD8+CTL expression in 120 HCC patients from our center. Survival analysis was performed using the Kaplan-Meier survival analysis with the Log rank test and was adopted to analyze immunotherapy outcomes correlated with Ku70/Ku80 expression in various solid tumors. Multivariate analysis of HCC patient data from our center was performed using a Cox proportional hazards model.

Increased Ku70/Ku80 expression positively correlated with more enriched immune microenvironment signatures, indicating increased immune infiltration in HCC. Upregulation of Ku70/Ku80 indicated better anti-PD1 and anti-PDL1 treatment outcomes in various solid tumors. Higher Ku70/Ku80 expression with lower CD8+CTL signatures indicated worse survival outcomes, whereas lower Ku70/Ku80 expression with higher CD8+CTL signatures indicated the best prognosis.

Higher Ku70/Ku80 expression indicated an immune-hot infiltration signature in HCC. Patients with increased Ku70/Ku80 expression and high CD8+CTL signatures may potentially benefit from CTL-centered immunotherapies.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, primarily developing in the context of chronic liver disease. Traditional prevention has focused on liver-specific interventions like antiviral therapies and surveillance. However, extrahepatic factors also significantly contribute to HCC risk. This review explores comprehensive strategies for HCC prevention, including both hepatic and extrahepatic factors.

An extensive literature search of peer-reviewed articles up to October 2024 was conducted, focusing on studies addressing HCC prevention strategies. Studies that focused on both hepatic and extrahepatic factors were included. Data were extracted and synthesized to provide an overview of current prevention strategies and their effectiveness in reducing HCC incidence.

Hepatitis B vaccination and antiviral treatments for hepatitis B and C significantly reduce HCC incidence. Lifestyle modifications-such as reducing alcohol consumption, maintaining a healthy weight through diet and exercise, and smoking cessation-are crucial in lowering HCC risk. Environmental measures to limit exposure to aflatoxins and other hazards also contribute to prevention. Regular surveillance of high-risk groups enables early detection and improves survival rates. Emerging strategies like immunotherapy and gene therapy show potential for further reducing HCC risk.

A comprehensive approach combining medical interventions, lifestyle changes, and environmental controls is essential for effectively decreasing HCC incidence globally. Implementing these combined measures could significantly reduce the global burden of HCC.

The heterogeneity of immune cells and metabolic pathways in hepatocellular carcinoma (HCC) patients has not been fully elucidated, leading to diverse clinical outcomes. Accurately distinguishing different HCC subtypes and recommending appropriate treatments is are highly important. In this study, we conducted a comprehensive analysis of 28 immune cells and 85 metabolic pathways in the TCGA-LIHC and GSE14520 datasets. Metabolism-related first principal component (MRPC1) and cytotoxic T lymphocyte (CTL) infiltration were used to assess the metabolic and immune infiltration levels of HCC patients, respectively. These two quantifiable indicators were then used to construct an immune‒metabolic classifier, which categorized HCC patients into three distinct groups. The potential biological mechanisms were explored through multiomics analysis, revealing that group S1 exhibited high metabolic activity and a high level of immune infiltration, that group S2 presented a low level of immune infiltration, and that group S3 presented low metabolic activity. This new immune‒metabolic classifier was well validated in a pancancer cohort of 9296 patients. The efficacy of multiple treatment approaches was assessed in relation to different immune‒metabolic groups, indicating that group S1 patients may benefit from immunotherapy, that group S2 patients are suitable for transcatheter arterial chemoembolization (TACE), and that group S3 patients are appropriate candidates for tyrosine kinase inhibitors. In conclusion, this immune‒metabolic classifier is anticipated to address the differences in treatment efficacy among HCC patients due to the heterogeneity of the tumor microenvironment, and to help refine the individualized treatment choices for clinical patients.

The optimal timing to discontinue immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) patients with clinical benefits remains unclear. This study aimed to assess the outcomes of HCC patients after ICI discontinuation.

Patients with HCC were retrospectively screened and those discontinued ICI therapy in the absence of progressive disease (PD) were included. Responses at discontinuation were evaluated per response evaluation criteria in solid tumors (RECIST) version 1.1 and modified RECIST (mRECIST). Patients were classified into five subgroups according to the cause of discontinuation: complete response (CR), partial response (PR), stable disease (SD) per RESICT version 1.1, adverse event (AE), or others. Progression-free survival (PFS) and overall survival (OS) since ICI start or after ICI discontinuation were assessed.

A total of 66 patients were included. The median follow-up was 29.33 months. The median PFS since ICI start was 30.83 months [95% confidence interval (CI): 24.93-36.72], and the median OS was not reached. The median PFS after discontinuation was 20.6 months (95% CI: 7.63-33.56), and the median OS after discontinuation was not reached. Univariate analysis showed that age, treatment after discontinuation, Response (RECIST version 1.1) at discontinuation and modified response (mResponse per mRECIST) at discontinuation were significantly associated with PFS after discontinuation, while age and mResponse at discontinuation were significantly associated with OS after discontinuation. Multivariate analysis further demonstrated that mResponse at discontinuation and treatment after discontinuation were independently associated with PFS after discontinuation, while age was independently associated with OS after discontinuation.

ICIs might be discontinued in HCC patients with a response of CR per mRECIST. Patients with a response of PR/SD per mRECIST or elder age could continue ICI therapy after achieving clinical benefits. Tyrosine kinase inhibitor (TKI) maintenance therapy might help to prevent progression after ICI discontinuation.

Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear.

Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC.

HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG.

We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies.

Immune checkpoint inhibitors (ICIs) are emerging treatments for advanced hepatocellular carcinoma (HCC); however, evidence has shown they may induce hyperprogressive disease via unexplained mechanisms.

In this study, we investigated the possible stimulative effect of ICIs on programmed cell death-ligand 1 (PD-L1)-harboring liver cancer cells under immunocompetent cell-free conditions.

The sarcomatous HAK-5 cell line displayed the highest expression of PD-L1 among 11 human liver cancer cell lines used in this study. HLF showed moderate expression, while HepG2, Hep3B, and HuH-7 did not show any. Moreover, sarcomatous HCC tissues expressed high levels of PD-L1. We observed approximately 20% increase in cell proliferation in HAK-5 cells treated with anti-PD-L1 antibodies, such as durvalumab and atezolizumab, for 48 h compared with that of those treated with the control IgG and the anti-PD-1 antibody pembrolizumab. No response to durvalumab or atezolizumab was shown in PD-L1-nonexpressing cells. Loss-of-function and gain-of-function experiments for PD-L1 in HAK-5 and HepG2 cells resulted in a significant decrease and increase in cell proliferation, respectively. Phosphorylated receptor tyrosine kinase array and immunoprecipitation revealed direct interactions between PD-L1 and AXL in tumor cells. This was stabilized by extrinsic anti-PD-L1 antibodies in a glycosylated PD-L1-dependent manner. Activation of AXL, triggering signal relay to the Akt and Erk pathways, boosted tumor cell proliferation both in vitro and in xenografted tumors in NOD/SCID mice.

Collectively, this suggests that anti-PD-L1 antibodies stimulate cell proliferation via stabilization of the PD-L1-AXL complex in specific types of liver cancer, including in HCC with mesenchymal components.

Therapeutic anti-PD-L1 antibodies promote cell proliferation by stabilizing the PD-L1-AXL complex in PD-L1-abundant neoplasms, including in HCC with mesenchymal components. Such a mechanism may contribute to the development of hyperprogressive disease.

Wagashi is a West African type cottage cheese locally prepared from cow milk. Wagashi like other milk products, is prone to microbial contamination, particularly by fungi. Many of these fungal species produce mycotoxins which are of serious public health concern. This work aimed to update the mycoflora profile and determine the concentrations of aflatoxin M1 and its health risk characterization due to the consumption of wagashi. Culturing the wagashi on mycological media (Oxytetracycline Glucose Yeast Extract OGYE, Dichloran Rose Bengal Chloramphenicol DRBC) caused a de-novo growth of the quiescent spores at 28-30 °C for 5-7 days. The analysis of AFM1 levels in the samples was done using High-Performance Liquid Chromatography connected to a Fluorescence detector (HPLC-FLD). The exposure and risk assessment to the AFMI levels were determined using deterministic models prescribed by the European Food Safety Authority (EFSA). The fungal counts ranged between 2.36-4.30 log10 CFU/g. In total, thirteen (13) fungal species from eight (8) genera were isolated from all wagashi samples. They are; Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, Fusarium verticillioides, Penicillium digitatum, Trichoderma harzianum, Aspergillus terreus, Rhodotorula mucilaginosa, Rhizopus stolonifer, Aspergillus fumigatus, Yeast sp., Mucor racemosus and Fusarium oligosporum belonging to the genera Fusarium, Aspergillus, Penicillium, Trichoderma, Rhodotorula, Rhizopus, Yeast, and Mucor. The AFM1 observed in the wagashi samples' analysis was low, ranging from 0.00 (Not Detected) ± 0.00 - 0.06 ± 0.002 µg/Kg. Risk assessments of AFM1 using deterministic models produced outcomes that ranged between 5.92 × 10-3- 0.14 ng/kg bw/day, 1.42 -44.35, 0-0.0323 ng aflatoxins/kg bw/day, and 1.51 × 10-3 - 9.69 × 10-4 cases/100,000 person/yr for estimated daily intake (EDI), margin of exposure (MOE), average potency, and cancer risks, respectively, for the age categories investigated. Fungal counts were interpreted as medium to high. It was also established that the consumption of wagashi may pose adverse health effects on all age categories in the selected zones of the study since all calculated MOE values were less than 100,000.

Atezolizumab plus bevacizumab is the preferred first-line treatment regimen for patients with advanced hepatocellular carcinoma. Limited data have shown promising results with the use of immune checkpoint inhibitors like nivolumab to downstage these patients for liver transplantation (LT). Here, we describe the first case of successful downstaging with atezolizumab plus bevacizumab in a patient with multifocal hepatocellular carcinoma and main portal vein tumoral thrombosis, followed by ABO-incompatible live donor LT. This illustrated case highlights that atezolizumab plus bevacizumab therapy may be a potential bridging tool for curative LT.

Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy.

CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC.

We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib.

The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a prevalent malignant cancer worldwide, characterized by high morbidity and mortality rates. Alpha-fetoprotein (AFP) is a glycoprotein synthesized by the liver and yolk sac during fetal development. However, the serum levels of AFP exhibit a significant correlation with the onset and progression of HCC in adults. Extensive research has demonstrated that the tumor microenvironment (TME) plays a crucial role in the malignant transformation of HCC, and AFP is a key factor in the TME, promoting HCC development. The objective of this review was to analyze the existing knowledge regarding the role of AFP in the TME. Specifically, this review focused on the effect of AFP on various cells in the TME, tumor immune evasion, and clinical application of AFP in the diagnosis and treatment of HCC. These findings offer valuable insights into the clinical treatment of HCC.

Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.

Spinster homologue 2 (SPNS2) is a transporter of sphingosine-1-phosphate (S1P), a bioactive lipid linked to cancer progression. We studied the link between SPNS2 gene expression, tumor aggressiveness, and outcomes in patients with hepatocellular carcinoma (HCC).

Gene expression in patients with HCC was analyzed from the Cancer Genome Atlas (TCGA) (n = 350) and GSE76427 (n = 115) as a validation cohort, as well as liver tissue cohort GSE6764 (n = 75).

High-SPNS2 HCC was significantly associated with high level of lymph-angiogenesis-related factors. SPNS2 expression was significantly higher in normal liver and early HCC versus advanced HCC (P < 0.02). High SPNS2 levels enriched immune response-related gene sets; inflammatory, interferon (IFN)-α, IFN-γ responses, and tumor necrosis factor (TNF)-α, interleukin (IL)-6/Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling, complement and allograft rejection, but did not significantly infiltrate specific immune cells nor cytolytic activity score. High-SPNS2 HCC enriched tumor aggravating pathway gene sets such as KRAS (Kirsten rat sarcoma virus) signaling, but inversely correlated with Nottingham histological grade, MKI67 (marker of proliferation Ki-67) expression, and cell proliferation-related gene sets. Further, high-SPNS2 HCC had significantly high infiltration of stromal cells, showing that low-SPNS2 HCC is highly proliferative. Finally, high-SPNS2 HCC was associated with better disease-free, disease-specific, and overall survival (P = 0.031, 0.046, and 0.040, respectively).

Although SPNS2 expression correlated with lymph-angiogenesis and other cancer-promoting pathways, it also enriched immune response. SPNS2 levels were higher in normal liver compared to HCC, and inversely correlated with cancer cell proliferation and better survival. SPNS2 expression may be beneficial in HCC patients despite detrimental in-vitro effects.

Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established.

To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies.

We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment.

In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events.

HCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable.

This trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 - 238, registered on 4 Feb 2020.

The peroxisome proliferator-activated receptor (PPAR) signaling pathway plays a crucial role in systemic cell metabolism, energy homeostasis and immune response inhibition. However, its significance in hepatocellular carcinoma (HCC) has not been well documented. In our study, based on the RNA sequencing data of HCC, consensus clustering analyses were performed to identify PPAR signaling pathway-related molecular subtypes, each of which displaying varying survival probabilities and immune infiltration status. Following, a prognostic prediction model of HCC was developed by using the random survival forest method and Cox regression analysis. Significant difference in survival outcome, immune landscape, drug sensitivity and pathological features were observed between patients with different prognosis. Additionally, decision tree and nomogram models were adopted to optimize the prognostic prediction model. Furthermore, the robustness of the model was verified through single-cell RNA-sequencing data. Collectively, this study systematically elucidated that the PPAR signaling pathway-related prognostic model has good predictive efficacy for patients with HCC. These findings provide valuable insights for further research on personalized treatment approaches for HCC.

Colon cancer (CC) has a high incidence rate. Radical resection is the main treatment method for CC; however, liver metastasis (LM) often occurs post-surgery. The liver contains both innate and adaptive immune cells that monitor and remove abnormal cells and pathogens. Before LM, tumor cells secrete cytokines and exosomes to adjust the immune microenvironment of the liver, thus forming an inhibitory immune microenvironment for colonization by circulating tumor cells. This indicates that the immune state of patients with CC plays a crucial role in the occurrence and progression of LM.

To observe and analyze the relationship between immune status and expression of tumor factors in patients with LM of CC, and to provide a scientific intervention method for promoting the patient prognosis.

A retrospective analysis was performed. The baseline data of 100 patients with CC and 100 patients with CC who suffered from postoperative LM and were admitted to our hospital from May 2021 to May 2023 were included in the non-occurrence and occurrence groups, respectively. The immune status of the patients and the expression of tumor factor-related indicators in the two groups were compared, and the predictive value of the indicators for postoperative LM in patients with CC was analyzed.

Compared with the non-occurrence group, the expression of serum carcinoembryonic antigen (CEA), CA19-9, CA242, CA72-4 and CA50 in patients in the occurrence group were significantly higher, while the expression of CD3+, CD4+, CD8+, natural killer (NK) and CD4+/CD25 in patients in the occurrence group were significantly lower (P < 0.05). No significant difference was observed in other baseline data between groups (P > 0.05). Multivariate logistic regression model analysis revealed that the expressions of CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 were associated with the LM in patients with CC. High expressions of serum CEA, CA19-9, CA242, CA72-4 and CA50, and low expressions of CD3+, CD4+, CD8+, NK, and CD4+/CD25 in patients with CC were risk factors for LM (OR > 1, P < 0.05). The receiver operating characteristic curve showed that the area under curve for CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 in the prediction of LM in patients with CC were all > 0.80, with a high predictive value.

The expression of tumor factors and immune state-related indices in patients with CC is closely associated with the occurrence of LM.

The development and progression of hepatocellular carcinoma (HCC) have been reported to be associated with immune-related genes and the tumor microenvironment. Nevertheless, there are not enough prognostic biomarkers and models available for clinical use. Based on seven prognostic genes, this study calculated overall survival in patients with HCC using a prognostic survival model and revealed the immune status of the tumor microenvironment (TME).

To develop a novel immune cell-related prognostic model of HCC and depict the basic profile of the immune response in HCC.

We obtained clinical information and gene expression data of HCC from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. TCGA and ICGC datasets were used for screening prognostic genes along with developing and validating a seven-gene prognostic survival model by weighted gene coexpression network analysis and least absolute shrinkage and selection operator regression with Cox regression. The relative analysis of tumor mutation burden (TMB), TME cell infiltration, immune checkpoints, immune therapy, and functional pathways was also performed based on prognostic genes.

Seven prognostic genes were identified for signature construction. Survival receiver operating characteristic curve analysis showed the good performance of survival prediction. TMB could be regarded as an independent factor in HCC survival prediction. There was a significant difference in stromal score, immune score, and estimate score between the high-risk and low-risk groups stratified based on the risk score derived from the seven-gene prognostic model. Several immune checkpoints, including VTCN1 and TNFSF9, were found to be associated with the seven prognostic genes and risk score. Different combinations of checkpoint blockade targeting inhibitory CTLA4 and PD1 receptors and potential chemotherapy drugs hold great promise for specific HCC therapies. Potential pathways, such as cell cycle regulation and metabolism of some amino acids, were also identified and analyzed.

The novel seven-gene (CYTH3, ENG, HTRA3, PDZD4, SAMD14, PGF, and PLN) prognostic model showed high predictive efficiency. The TMB analysis based on the seven genes could depict the basic profile of the immune response in HCC, which might be worthy of clinical application.

Hepatocellular carcinoma (HCC) is the third leading cause of global cancer-related deaths. Despite immunotherapy offering hope for patients with HCC, only some respond to it. However, it remains unclear how to pre-screen eligible patients. Our study aimed to address this issue. In this study, we identified 13 prognostic genes through univariate Cox regression analysis of 87 apoptosis-related genes. Subsequently, these 13 genes were analyzed using ConsensusClusterPlus, and patients were categorized into three molecular types: C1, C2, and C3. A prognostic model and RiskScore were constructed using Lasso regression analysis of 132 significant genes identified between C1 and C3. We utilized quantitative polymerase chain reaction to confirm the model's transcript level in Huh7 and THLE2 cell lines. Both molecular subtypes and RiskScores effectively predicted patients benefiting from immunotherapy. Cox regression analysis revealed RiskScore as the most significant prognosis factor, suggesting its clinical application potential and providing a foundation for future experimental research.

The prognostic significance of the ratio of activated CD4 T cells to Tregs infiltrating tumor tissues in gastric cancer (GC) remains unknown.

For the quantification of infiltration of immune cells, the ssGSEA algorithm, which is a single sample gene set enrichment analysis, was utilized. Group A was defined as having activated CD4 T cells/Tregs >1, while group B was defined as having activated CD4 T cells/Tregs <1. To compare the overall survival (OS) of the two groups, the Kaplan-Meier survival analysis was employed. The R package 'limma' was used to identify the immune and metabolism related genes that were expressed differentially between the two groups, with a false discovery rate (FDR) less than 0.05. The risk score (RS) was constructed by combining univariate Cox regression analysis, LASSO penalized Cox regression analysis, and multivariate Cox regression analysis. The median RS was used to classify high-risk (HR) and low-risk (LR) groups.

A predicted unfavorable outcome of GC was observed when the ratio of activated CD4 T cells to Tregs was less than 1. Our proposed RS was utilized for prognostic risk categorization in ten distinct independent cohorts (TCGA-STAD, n = 371; GSE84437, n = 433; GSE26253, n = 432; GSE13861, n = 65; GSE15459, n = 192; GSE26899, n = 93; GSE26901, n = 109; GSE28541, n = 40; GSE34942, n = 56; GSE62254, n = 300) and exhibited exceptional precision. In terms of tumor microenvironment (TME) and treatment strategies, compared to the LR group, the HR group was characterized by a higher infiltration levels of stromal cells, Tregs, macrophages, Tfh, mast cells, and NK cells, inclined to activated CD4 T cells/Tregs <1, and exhibited insensitivity to immunotherapy and multiple chemotherapy drugs. In relation to the potential molecular mechanism, the excessive activation of oncogenic pathways such as MAPK, hedgehog, WNT, calcium, and TGF-β signaling pathways may accelerate the malignant progression of GC by stimulating angiogenesis, promoting EMT, and altering ECM. Conversely, the overactivation of the P53 pathway is likely to inhibit tumor proliferation by regulating the cell cycle.

The immune-metabolism signature associated with the ratio of activated CD4 T cells and Tregs could be used to assess prognosis, TME, and treatment strategies in GC patients.

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.

To analyze the clinical characteristics and influencing factors of hepatotoxicity in patients with advanced hepatocellular carcinoma (HCC) treated with programmed cell death protein-1 (PD-1) inhibitors, and to provide a theoretical basis for the treatment of immune-related hepatotoxicity in patients with advanced HCC.

Retrospective analysis of clinical data of patients with advanced HCC from February 2021 to February 2023, in order to summarize and statistically analyze the influencing factors of immune-related liver adverse reactions.

A total of 135 patients met the inclusion criteria, among whom 46 patients experienced varying degrees of immune-related liver adverse reactions, with an incidence rate of 34.1% (46/135). The time range of immune-related liver adverse reactions was 3-26 weeks, with a median time of 4 weeks. The age range of immune-related liver adverse reactions was 34-73 years, with a median age of 62 years. Statistical analysis of the influencing factors and liver adverse reactions showed that age, total bilirubin level, and Child-Pugh (C-P) grading were influencing factors for the occurrence of liver adverse reactions (p < .05), and among these three influencing factors, the proportion of males with ≥2 influencing factors was higher than that of females; liver function C-P B was an independent influencing factor for liver adverse reactions (p < .05).

For male patients over 60 years old, with bilirubin levels ≥51 μmol/L and liver function C-P B, close observation of the occurrence of immune-related adverse reactions during treatment is recommended.

Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) remain poorly understood.

We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns. Subsequently, we examined variations in the overall survival (OS), genomic profiles, and TME characteristics between these subtypes. To develop a prognostic coagulation-related risk score (CRRS) model, we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses. We also created a nomogram to aid in the clinical application of the risk score, evaluating the relationships between the CRRS and the immune microenvironment, responsiveness to immunotherapy, and targeted treatment. The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed.

There were significant differences in clinical features, prognostic stratification, genomic variation, and TME characteristics between the two coagulation-related subtypes. We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients. Significant variations in survival outcomes were observed between the high- and low-risk groups. The nomogram was proficient in predicting the 1-, 3-, and 5-year OS. Additionally, the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC. Moreover, we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis. PLAUR knockdown notably inhibited ccRCC cell proliferation and migration.

Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.

Hepatocellular carcinoma (HCC) is the most prevalent malignant tumor worldwide. Within HCC's tumor microenvironment, focal adhesion kinase (FAK) plays a critical role. Regulatory T cells (Treg) modulate the polarization of tumor-associated macrophages , but the relationship between FAK, Treg cells, and macrophages remains underexplored. Phellinus linteus (PL) shows promise as a treatment for HCC due to its pharmacological effects. This study aimed to explore the relationship between FAK and Treg-macrophages and to assess whether PL could exert a protective effect through the FAK process in HCC. Initially, C57BL/6-FAK-/- tumor-bearing mice were utilized to demonstrate that FAK stimulates HCC tumor development. High dosages (200 μM) of FAK and the FAK activator ZINC40099027 led to an increase in Treg (CD4+CD25+) cells, a decrease in M1 macrophages (F4/80+CD16/32+, IL-12, IL-2, iNOS), and an increase in M2 macrophages (F4/80+CD206+, IL-4, IL-10, Arg1, TGF-β1). Additionally, FAK was found to encourage cell proliferation, migration, invasion, and epithelial-mesenchymal transition while inhibiting apoptosis in HepG2 and SMMC7721 cells. These effects were mediated by the PI3K/AKT1/Janus Kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase (p38 MAPK)/Jun N-terminal Kinase (JNK) signaling pathways. Furthermore, PL exhibited a potent antitumor effect in vivo in a dose-dependent manner, reducing FAK, Treg cells, and M2 macrophages, while increasing M1 macrophages. This effect was achieved through the inhibition of the PI3K/AKT/JAK/STAT3, and p38/JNK pathways. Overall, our findings suggest that FAK promotes HCC via Treg cells that polarize macrophages toward the M2 type through specific signaling pathways. PL, acting through FAK, could be a protective therapy against HCC.

Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and a nonnegligible health concern on a worldwide scale. Disulfidptosis is a novel mode of cell death, which is mainly caused by the collapse of the actin skeleton. Although many studies have demonstrated that various types of cell death are associated with cancer treatment, the relationship between disulfidptosis and HCC has not been elucidated.

Here, we mainly applied bioinformatics methods to construct a disulfidptosis related risk model in HCC patients. Specifically, transcriptome data and clinical information were downloaded from the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) database. A total of 45 co-expressed genes were extracted between the disulfidptosis-related genes (DRGs) and the differential expression genes (DEGs) of liver hepatocellular carcinoma (LIHC) in the TCGA database. The LIHC cohort was divided into two subgroups with different prognosis by k-mean consensus clustering and functional enrichment analysis was performed. Subsequently, three hub genes (CDCA8, SPP2 and RDH16) were screened by Cox regression and LASSO regression analysis. In addition, a risk signature was constructed and the HCC cohort was divided into high risk score and low risk score subgroups to compare the prognosis, clinical features and immune landscape between the two subgroups. Finally, the prognostic model of independent risk factors was constructed and verified.

High DRGs-related risk score in HCC individuals predict poor prognosis and are associated with poor immunotherapy response, which indicates that risk score assessment model can be utilized to guide clinical treatment strategy.

Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.

Hepatocellular carcinoma (HCC) is a severe malignant liver cancer with a poor prognosis and a high mortality rate. This carcinoma is a multistage process that begins with chronic hepatitis and progresses to cirrhosis, dysplastic nodules, and eventually HCC. However, the exact molecular etiology remains unclear. MicroRNAs (miRs) are small non-coding RNAs that modulate the expression of numerous genes. These molecules have become significant participants in several functions, including cell proliferation, differentiation, development, and tumorrelated properties. They have a pivotal role in carcinogenesis as oncogenes or tumor suppressor genes. Furthermore, some investigations have shown that particular miRs might be used as predictive or diagnostic markers and therapeutic targets in HCC therapy. This review study summarizes the current level of knowledge on the role of miRs in the initiation and progression of HCC.