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The prediction of liver-related events (LRE) after sustained virological response (SVR) in HCV-advanced chronic liver disease (ACLD) patients is crucial. We aimed to evaluate incidence and risk factors of LRE in HCV-cirrhotic patients after SVR and to assess dynamic changes of liver stiffness in participants without LRE at the end of follow-up. We enrolled 575 consecutive patients with HCV-ACLD treated with DAAs and followed up for 5 years after SVR12. Overall, 98 (17%) patients developed any type of event, and HCC was the most frequent LRE. The incidence rate was 1.6 per 100 person-years (p/y) for both HCC and hepatic decompensation. Baseline LSM ≥ 20 kPa was the only independent predictor of hepatic decompensation, while LSM ≥ 20 kPa and male sex were independent predictors of HCC development. Among the 341 participants without LRE and with paired LSM, any LSM reduction was observed in 314 (92.1%), and half of them showed a decrease of LSM ≥ 20%. Among patients without LRE, 27.3% of participants without ≥20% LSM decrease at 2 years achieved the 5-year goal; in contrast, 31.6% of participants with ≥20% LSM decrease at 2 years lost it at 5 years. These findings provide evidence that baseline LSM is a tool to stratify patients at risk of developing LRE; the dynamic changes of LSM value suggest the need for monitoring this parameter over time. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection remains a major public health concern worldwide, with approximately 296 million individuals chronically infected. The HBV-encoded X protein (HBx) is a regulatory protein of 17 kDa, reportedly responsible for a broad range of functions, including viral replication and oncogenic processes. In this review, we summarize the state of knowledge on the mechanisms underlying HBx functions in viral replication, the antiviral effect of therapeutics directed against HBx, and the role of HBx in liver cancer development (including a hypothetical model of hepatocarcinogenesis). We conclude by highlighting major unanswered questions in the field and the implications of their answers. [ABSTRACT FROM AUTHOR]

Sarcopenia and frailty are common complications in patients with cirrhosis evaluated for liver transplantation (LT). Although the negative impact of sarcopenia on patient's outcome has been well studied, the prognostic role of frailty is not as clear. We assessed the prevalence of sarcopenia and frailty and the clinical impact of frailty in a prospective cohort of cirrhosis patients with and without hepatocellular carcinoma (HCC) listed for LT. Patients with cirrhosis were prospectively recruited at the time of admission into the waiting list. Clinical and lab values were collected. Physical frailty was assessed by liver frailty index (LFI) and patients were categorized into robust (< 3.2); pre-frail (between 3.2 and 4.5), and frail (> 4.5). Skeletal muscle mass was evaluated via skeletal muscle index (SMI) obtained from last CT scan before LT; sarcopenia was defined by SMI < 50 cm2/m2 in males and < 39 cm2/m2 in females. 105 patients were included, of which 42 (40%) had hepatocellular carcinoma (HCC). In patients without HCC (63.5% males, median age 61 years), 36.5% were frail, 50.8% were pre-frail and 12.7% were robust. Frail patients were older than non-frail patients (63 vs. 56; p = 0.008) and had more severe liver disease (Child C: 65% vs. 37.5%; p = 0.02). Prevalence of sarcopenia in patients without HCC was 63%, with similar value of median SMI between frail and not frail patients (p = 0.454). Patients with HCC (78.6% males, 65 years old) were 21.4% frail, 61.9% pre-frail, and 16.7% robust. Frail patients had more severe liver disease (Child C: 77% vs. 18.2%; p = 0.004), whereas age was comparable to non-frail patients; among patients without HCC, during a median follow-up of 263 days, 17% died (of which 72% were frail) and 10 patients were delisted due to clinical improvement (none of whom were frail). Among those with HCC, during a median follow-up of 289 days, 4 (9%) patients died of which 50% were frail. Frailty and sarcopenia are common complications in patients with cirrhosis awaiting LT. Frailty appears to be associated with an increased risk of mortality during wait-list time especially in those with decompensated cirrhosis. At univariate analysis Meld score, Child score and presence of frailty were found to be associated with shorter survival, however, at multivariate analysis presence of frailty and Child C vs. A/B were the only independent predictor of death. Larger cohorts are required to confirm these results. [ABSTRACT FROM AUTHOR]

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Atezolizumab (TECENTRIQ®) and nivolumab (OPDIVO®) are both immunotherapeutic indications targeting programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1), respectively. These inhibitors hold promise as therapies for triple-negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) and have demonstrated encouraging results in reducing the progression and spread of tumors. However, due to their adverse effects and low response rates, the US Food and Drug Administration (FDA) has withdrawn the approval of atezolizumab in TNBC and nivolumab in HCC treatment. The withdrawals of atezolizumab and nivolumab have raised concerns regarding their effectiveness and the ability to predict treatment responses. Therefore, the current study aims to investigate the immunotherapy withdrawal of PD-1/PD-L1 inhibitors, specifically atezolizumab for TNBC and nivolumab for HCC. This study will examine both the structural and clinical aspects. This review provides detailed insights into the structure of the PD-1 receptor and its ligands, the interactions between PD-1 and PD-L1, and their interactions with the withdrawn antibodies (atezolizumab and nivolumab) as well as PD-1 and PD-L1 modifications. In addition, this review further assesses these antibodies in the context of TNBC and HCC. It seeks to elucidate the factors that contribute to diverse responses to PD-1/PD-L1 therapy in different types of cancer and propose approaches for predicting responses, mitigating the potential risks linked to therapy withdrawals, and optimizing patient outcomes. By better understanding the mechanisms underlying responses to PD-1/PD-L1 therapy and developing strategies to predict these responses, it is possible to create more efficient treatments for TNBC and HCC. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Bioinformatics analysis of hepatocellular carcinoma (HCC) expression profiles can aid in understanding its molecular mechanisms and identifying new targets for diagnosis and treatment. Aim In this study, we analyzed expression profile datasets and miRNA expression profiles related to HCC from the GEO using R software to detect differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs). Methods and results Common DEGs were identified, and a PPI network was constructed using the STRING database and Cytoscape software to identify hub genes. The reduced levels of tumor suppressor miRNAs or down regulated DEmiRs may be increased levels of oncogenes, the oncomirs or up regulated DEmiRs may be decreased levels of tumor suppressor genes in cancerous cells. According to this strategy, increased and decreased DEGs, also increased and decreased DEmiRs were selected. The multimir package was employed to predict target genes for DEmiRs then DEmiRs‐hub gene network created. We identified approximately 1000 overlapping DEGs and 60 DEmiRs. Hub genes included RRM2, MELK, KIF11, KIF23, NCAPG, DLGAP5, BUB1B, AURKB, CCNB1, KIF20A, CCNA2, TTK, PBK, TOP2A, CDK1, MAD2L1, BIRC5, ASPM, CDCA8, and CENPF, all associated with significantly worse survival in HCC. miR‐224, miR‐24, miR‐182, miRNA‐1‐3p, miR‐30a, miR‐27a, and miR‐214 were identified as important DEmiRs with targeting more than six hub genes. Conclusion Generally, our findings offer insight into the interaction of hub genes and miRNAs in the development of HCC by bioinformatics analysis, information that may prove useful in identifying biomarkers and therapeutic targets in HCC.

Globally, primary liver cancer (PLC) ranks the most fatal malignancy. Most of the patients are in advanced stage of PLC at the very time they are diagnosed with it, accounting much for its poor prognosis. With the advancement of modern medical research and care system, the main etiology of PLC more and more switches from hepatitis viruses such as HAV, HBV, HCV, HEV to other causes like metabolism-associated steatohepatitis (MASH) and metabolic-associated fatty liver disease (MAFLD). As a result, it is of great necessity to find out new ways for treatment and early diagnosis to cope with this problem. Nowadays, as the mechanism of the Gut-Liver Axis in the formation of MAFLD, MASH and PLC has been gradually elucidated. The association between gut microbiome and the formation of PLC is of great significance to take an insight into. In this review, we present the concept of Gut-Liver Axis and its function in the mutual influence between gut microbiota and PLC from several aspects in which we will focus on the structure of gut barrier and the functional influences the gut microbiota have on the immune response and metabolic changes on human liver. Furthermore, we conclude the potential association of gut microbiota constitution with the PLC. Eventually, we hope this review can offer novel instructions for early diagnosis and treatment for liver cancer.

PurposeTo provide a detailed pooled analysis of the diagnostic accuracy of microRNAs (miRNAs) in predicting the response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).MethodsA comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science to identify studies assessing the diagnostic performance of miRNAs in predicting TACE response in HCC. Two independent reviewers performed quality assessment and data extraction using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve were calculated using a bivariate random-effects model. Subgroup analyses and meta-regression were performed to explore potential sources of heterogeneity, including sample size, response criteria, specimen source, response evaluation methods, TACE efficacy interval window, and geographical location.ResultsSeven studies, comprising 320 HCC responders and 187 non-responders, were included in this meta-analysis. The miRNAs studied included miR-373, miR-210, miR-4492, miR-1271, miR-214, miR-133b, and miR-335. The pooled sensitivity of miRNAs in predicting recurrence after TACE was 0.79 [95% CI: 0.72-0.84], and the pooled specificity was 0.82 [95% CI: 0.74-0.88]. The DOR was 17 [95% CI: 9-33], and the pooled area under the SROC curve (AUC) was 0.85 [95% CI: 0.81-0.88], indicating excellent diagnostic accuracy. Subgroup analyses revealed significant differences in diagnostic performance based on response criteria and geographical location. Meta-regression did not identify any significant sources of interstudy heterogeneity.ConclusionMiRNAs show promise as diagnostic tools for predicting TACE response in HCC patients. However, their clinical application requires further validation in larger cohorts. Future research should focus on standardizing RNA extraction methods, selecting consistent endogenous controls, and adopting uniform response evaluation criteria to improve reliability and reduce variability.

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent causes of cancer-related morbidity and mortality worldwide. Late-stage detection and the complex molecular mechanisms driving tumor progression contribute significantly to its poor prognosis. Dysregulated R-loops, three-stranded nucleic acid structures associated with genome instability, play a key role in the malignant characteristics of various tumors. However, the detailed role and mechanism of R-loops in HCC progression remain elusive and require further exploration. This study aimed to construct an R-loop scoring signature centered on prognosis and lipid metabolism, thereby enhancing our understanding of HCC progression and identifying potential therapeutic targets.MethodsIn this study, we utilized the single-cell RNA-sequencing (scRNA-seq) data from HCC patients (GSE149614 and CRA002308) to construct an R-loop scoring model based on the identified R-loop regulator genes (RLRGs) related to HBV infection through WGCNA analysis. We also explored the tumor microenvironment and intercellular communication related to R-loop score. Additionally, a prognostic risk model based on the fatty acid metabolism-associated RLRGs was constructed using data from the TCGA database, and its association with immune infiltration, mutations, and drug sensitivity was analyzed. In vitro and in vivo experiments were performed to investigate the role of RLRG CLTC in lipid metabolism and HCC progression.ResultsUsing scRNA-seq data from HCC, we established an R-loop scoring model based on identified RLRGs related to HBV infection. Moreover, the more suppressive tumor immune microenvironment and stronger intercellular communication were displayed in malignant cells with high R-loop scores. The cell trajectory and cellular metabolism analysis exhibited a significant association between lipid metabolism and RLRGs. Additionally, we constructed a prognostic risk model consisting of 8 RLRGs related to fatty acid metabolism, which effectively evaluated the prognostic value, status of tumor immune microenvironment, gene mutations, and chemotherapeutic drug sensitivity for HCC patients. Notably, validation experiments suggested that CLTC could regulate lipid metabolism through R-loop formation and facilitate tumor progression in HCC.ConclusionCollectively, our study proposes an R-loop scoring model associated with tumor immune microenvironment, lipid metabolism and prognostic value. CLTC, an R-loop regulator, emerges as a promising prognostic biomarker and therapeutic target, offering new insights into potential treatment strategies for HCC patients.

BackgroundElevated levels of carbohydrate antigen 19-9 (CA19-9) levels are known to worsen outcomes in various tumors by influencing immune responses. However, the role of CA19-9 in immunotherapy for hepatocellular carcinoma (HCC) remains poorly understood.MethodsThis study included 621 patients treated with anti-PD-1/PD-L1 treatment at the First Affiliated Hospital of Sun Yat-sen University from January 2017 to March 2023. During immunotherapy, CA19-9 levels were measured and classified as either elevated (≥35 U/mL) or normal (

BackgroundSorafenib is a first-line treatment for hepatocellular carcinoma (HCC); however, acquired resistance often results in a poor prognosis, indicating a need for more effective therapies. Sorafenib induces cell death through an iron-dependent mechanism known as ferroptosis, which is closely associated with the onset and progression of HCC.MethodsThis study investigated the role of ACSL3 in sorafenib resistance and ferroptosis in HCC. The expression of ACSL3 was analyzed in HCC tissues and cell lines. Ferroptosis levels and cell viability were assessed in ACSL3-silenced HCC cells treated with sorafenib. The regulatory relationship between the transcription factor MEF2D and ACSL3 was evaluated using promoter binding assays and gene expression analysis.ResultsACSL3 was aberrantly expressed in HCC and promoted the progression of non-alcoholic fatty liver disease (NAFLD) to HCC. Elevated ACSL3 expression inhibited ferroptosis and enhanced resistance to sorafenib. The transcription factor MEF2D directly regulated the upregulation of ACSL3 expression. MEF2D bound to the promoter regions of ACSL3 to enhance its transcription and negatively regulate ferroptosis in HCC.ConclusionThis study demonstrated for the first time that MEF2D regulated ACSL3 expression and mediated sorafenib resistance by inhibiting ferroptosis in HCC, providing a potential therapeutic target for improving HCC outcomes.

Purpose: Hepatocellular carcinoma (HCC) resistance to sorafenib treatment and other treatment strategies causes a higher mortality rate in patients diagnosed with HCC.Research question.HCC often develops resistance to sorafenib treatment and other therapies, leading to increased mortality rates in diagnosed patients. Herein, we propose a combined therapeutic approach using rosiglitazone, a key factor in cellular differentiation, along with adipogenesis inducers such as dexamethasone, IBMX, and insulin. Additionally, we included sorafenib, a primary drug for liver cancer treatment, in this combination cocktail and carried out the differentiation process in the presence of sorafenib. Results: Our study demonstrates that this combination induces the formation of adipocytes from HCC cells over several days under specific conditions and steps. Conclusion. findings suggest that supplementing sorafenib with rosiglitazone and adipogenesis inducers may potentially transform HCC cells into adipocyte-like cells. Fat could be “the good” in the story of liver cancer alleviation, demonstrating the role of rosiglitazone.

BackgroundProgrammed death-ligand 1 (PD-L1) expression is abundant not only in malignant cells but also in infiltrating cells within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). This study explored the association between PD-L1 expression in TME and outcomes in HCC patients treated with atezolizumab plus bevacizumab (AB), emphasizing the implications of PD-L1 expression in both malignant and tumor-infiltrating cells.MethodsThis study included 72 patients with HCC who underwent percutaneous core needle liver biopsy before AB treatment between September 2020 and December 2023. PD-L1 expression on tumor tissues was assessed using the combined positive score (CPS) with cutoff values of 1 and 10, utilizing antibody clone 22C3 (Dako).ResultsThe distribution of PD-L1 CPS included 24 patients with CPS

BackgroundHuman leukocyte antigen-G (HLA-G) is a cancer-associated immune checkpoint protein implicated in tumor-driven immune escape mechanisms. This study was undertaken to determine genetic variations at the 3’-UTR of the HLA-G gene that may alter its expression, identify risk alleles and genotypes for their association with hepatocellular carcinoma (HCC), and treatment responses in the Indian population.ObjectivesCase-control genetic association study of HLA-G gene UTR polymorphisms with HCC and response to locoregional therapy (LRT).MethodsHCC cases (n = 100) and healthy controls (n = 110) were recruited for the genetic association study, of which 88 patients received LRT. Single nucleotide polymorphisms (SNPs) at the HLA-G 3’-UTR gene were genotyped by sequencing and PCR-RFLP. The genetic association of 14 SNPs with HCC and LRT responses was determined using population genetic approaches.ResultsThree of the 14 SNPs (rs1707, rs1710, and rs1063320) were found to be genetically associated with HCC risk and treatment responses. These three UTR SNPs are important for miRNA binding. We did not observe significant association of the most studied SNP, rs371194629 (INDEL, +2960), with HCC or treatment response. Serum sHLA-G levels were found to be significantly (p = 0.027) higher in HCC patients as compared to healthy controls. Highly prevalent UTR haplotypes in Indian HCC patients were UTR-4, -1, and -7 whereas in healthy controls it was UTR-3, and 15 as determined by a linkage disequilibrium (LD) plot using 8 SNPs.ConclusionHLA-G SNPs are genetically associated with HCC and treatment response. Haplotypes associated with high levels of HLA-G expression are more prevalent in HCC than in healthy controls.Core tipPopulation genetic approaches were used to study HLA-G gene polymorphisms in the Indian population for its genetic association with HCC risk, treatment response and altered gene expression. Out of the 14 SNPs studied for HLA-G UTR, three were linked to HCC and response to locoregional therapy. Linkage disequilibrium and UTR haplotyping analysis show that the UTR-4 haplotype linked to high HLA-G levels, is more common in HCC patients, while the UTR-3 haplotype, linked to low HLA-G levels, is more common in healthy controls. This study is the first to look at the UTR types based on HLA-G gene polymorphisms of Indian HCC patients and their response to therapy.

Hepatocellular carcinoma (HCC) exhibits a subtle onset, high incidence rates, and low survival rates, becoming a substantial threat to human health. Hence, it is crucial to discover fresh biomarkers and treatment targets for the early detection and management of HCC. CCK-8, scratch-wound, and transwell assays were used to evaluate the biological properties of HCC cell lines (Huh-7 and Hep3B). Bioinformatics analysis identified the downstream target mRNA of miR-145-5p as acyl-CoA synthetase long-chain family member 4 (ACSL4). RT-qPCR was used to test miR-145-5p and ACSL4 levels. Transwell chambers were used to co-incubate purified CD8+ T cells and HCC cells for 48 h, and the effect of CD8+ T cells on apoptosis in HCC cells was detected by flow cytometry. A subcutaneous graft tumor model was constructed, and ELISA kits were used to assess cytokine levels and CD8+ T cell activation markers. HCC cells showed a decline in miR-145-5p levels and a rise in ACSL4 levels. Overexpression of miR-145-5p hindered HCC cell proliferation, migration, and invasion, while stimulating CD8+ T cell activation. Conversely, overexpression of ACSL4 enhanced the malignant biological properties of HCC cells and reduced the effect of CD8+ T cells, while silencing ACSL4 had the opposite effect. miR-145-5p targeted and downregulated ACSL4, while overexpression of miR-145-5p weakened the promotion of HCC malignant progression caused by ACSL4 overexpression. Additionally, overexpression of miR-145-5p and silencing ACSL4 were effective in inhibiting tumor growth in vivo. In conclusion, miR-145-5p targets and downregulates ACSL4, leading to the inhibition of HCC malignant progression and preventing immune escape in HCC cells.

Metastasis accounts for the vast majority of cancer deaths; however, this complex process has yet to be fully explained. To form metastases, cancer cells must undergo a series of steps, known as the “Metastatic cascade”, each of which requires a specific functional transformation. Cancer stem cells (CSCs) play a vital role in tumor metastasis, but their dynamic behavior and regulatory mechanisms have not been fully elucidated. Based on the “Metastatic cascade” theory, this review summarizes the effect of liver CSCs on the metastatic biological programs that underlie the dissemination and metastatic growth of cancer cells. Liver CSCs have the capacity to initiate distant organ metastasis via EMT, and the microenvironment transformation that supports the ability of these cells to disseminate, evade immune surveillance, dormancy, and regenerate metastasis. Understanding the heterogeneity and traits of liver CSCs in these processes is critical for developing strategies to prevent and treat metastasis of advanced hepatocellular carcinoma (HCC).

NLRC5, the largest member of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family, has been reported to participate in the regulation of immune function and is associated with chronic inflammatory diseases. However, the biological function of NLRC5 in hepatocellular carcinoma (HCC) has not been fully demonstrated. The aim of this study is to evaluate NLRC5 expression in the tumor tissues of HCC patients undergoing surgical treatment, assess its prognostic value, and explore its relationship with critical immune-related molecules within the tumor microenvironment. A total of 100 patients with hepatitis B virus-associated HCC receiving surgical treatment were enrolled in the study. Immunohistochemical results were obtained by scoring the intensity of cellular staining and the percentage of positive cells in the tissue sections. The association between NLRC5 expression levels and the main clinicopathological factors was analyzed by Chi-square test method. The prognostic values were analyzed by COX regression model and the Kaplan-Meier survival curve. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of NLRC5 in postoperative patients with HCC. IHC showed that high expression of NLRC5 was observed in 67% of HCC tissue samples. Chi-square test showed that NLRC5 was a risk factor associated with tumor number, satellite nodule, and envelope invasion. Kaplan-Meier survival curves and COX survival analysis showed that high expression of NLRC5 was significantly associated with decreased overall survival (OS) in HCC patients (HR = 1.79, 95% CI 1.03–3.12, p = .041). However, univariate logistic regression analysis revealed that NLRC5 showed positive relationship with GZMB and CD8α suggesting its role in immune escape of HCC. ROC curve analysis showed that the combination of tumor number, envelope invasion, and NLRC5 expression (area under the curve = 0.824, sensitivity = 77.30%, specificity = 82.4%) can more accurately evaluate the prognosis of HCC patients compared to the combination of only tumor number and envelope invasion (area under the curve = 0.690, sensitivity = 43.9%, specificity = 94.1%).NLRC5 plays a crucial role in progression of HCC and can be considered as a potential prognostic and predictive biomarker. Targeting NLRC5 may provide an attractive therapeutic approach for HCC.

Hepatitis B virus (HBV) infection poses a challenge to global public health. Persistent liver infection with HBV is associated with an increased risk of developing severe liver disease. The complex interaction between the virus and the host is the reason for the persistent presence of HBV and the risk of tumor development. Chronic liver inflammation, integration of viral genome with host genome, expression of HBx protein, and viral genotype are all key participants in the pathogenesis of hepatocellular carcinoma (HCC). Epigenetic regulation in HBV-associated HCC involves complex interactions of molecular mechanisms that control gene expression and function without altering the underlying DNA sequence. These epigenetic modifications can significantly affect the onset and progression of HCC. This review summarizes recent research on the epigenetic regulation of HBV persistent infection and HBV-HCC development, including DNA methylation, histone modification, RNA modification, non-coding RNA, etc. Enhanced knowledge of these mechanisms will offer fresh perspectives and potential targets for intervention tactics in HBV-HCC.

Background & aimsHepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown.MethodsHepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) and control MUP-uPA/Atf4F/F mice were fed a high-fat diet to induce NASH-related HCC, and Atf4F/F and Atf4Δhep mice were injected with diethylnitrosamine to model carcinogen-induced HCC. Histological, biochemical, and RNA-sequencing analyses were performed to identify and define the role of ATF4-induced solute carrier family 7a member 11 (SLC7A11) expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development.ResultsHepatocyte ATF4 ablation inhibited hepatic steatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine/glutamate antiporter xCT, which is needed for glutathione synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of patients with NASH.ConclusionsDespite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production, ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset.Impact and implicationsLiver cancer or hepatocellular carcinoma (HCC) is associated with multiple aetiologies. Most HCC aetiologies cause hepatocyte stress and death, as well as subsequent inflammation, and compensatory proliferation, thereby accelerating HCCdevelopment. The contribution of individual stress effectors to HCC and their underlying mechanisms of action were heretofore unknown. This study shows that the stress-responsive transcription factor ATF4 blunts liver damage and cancer development by suppressing iron-dependent cell death (ferroptosis). Although ATF4 ablation prevents hepatic steatosis, it also increases susceptibility to ferroptosis, due to decreased expression of the cystine/glutamate antiporter SLC7A11, whose expression in human HCC and NASH correlates with ATF4. These findings reinforce the notion that benign steatosis may be protective and does not increase cancer risk unless accompanied by stress-induced liver damage. These results have important implications for prevention of liver damage and cancer.

Xin Qiu,1,2,&ast; Shuang Shen,1,&ast; Donghong Lu,2 Nizhen Jiang,3 Yifei Feng,3 Jindu Li,1 Chenglei Yang,1 Bangde Xiang1,4,5 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 4Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, People’s Republic of China; 5Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bangde Xiang; Chenglei Yang, Email xiangbangde@gxmu.edu.cn; chenglei2017yang@163.comBackground: Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its poor prognosis and high recurrence rates post-surgery. This study examines the predictive efficacy of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the post-hepatectomy prognosis of patients with HCC.Methods: A cohort comprising 1654 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital from 2013 to 2019 was enrolled. Patients were stratified into two groups according to the median ALI level, and then subjected to propensity score matching (PSM) in a 1:1 ratio. Kaplan-Meier survival curves, the traditional Cox proportional hazards (CPH) model, and machine learning (ML) models were employed to analyze and evaluate ALI’s prognostic significance. Furthermore, ALI’s prognostic value in digestive system tumors was validated via analysis of the National Health and Nutrition Examination Survey (NHANES) database.Results: After applying PSM, a final cohort of 1284 patients, categorized into high and low ALI groups, revealed a significantly reduced survival time in the low ALI cohort. Univariate and multivariate Cox analyses identified ALI, BCLC stage, CK19, Hepatitis B virus (HBV) DNA, lymph node metastasis, and microvascular invasion (MVI) as independent predictors of prognosis. Both traditional CPH and ML models incorporating ALI demonstrated excellent predictive accuracy, validated through calibration curves, time-dependent ROC curves, and decision curve analysis. Furthermore, the prognostic value of ALI in digestive tumors was confirmed in the NHANES database.Conclusion: The ALI exhibits potential as a prognostic predictor in patients with HCC following hepatectomy, providing valuable insights into postoperative survival.Keywords: advanced lung cancer inflammatory index, ALI, hepatocellular carcinoma, HCC, prognosis, Cox regression, machine learning, ML

Protein tyrosine phosphorylation is a post-translational modification that regulates protein structure to modulate demic organisms’ homeostasis and function. This physiological process is regulated by two enzyme families, protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). As an important regulator of protein function, PTPs are indispensable for maintaining cell intrinsic physiology in different systems, as well as liver physiological and pathological processes. Dysregulation of PTPs has been implicated in multiple liver-related diseases, including chronic liver diseases (CLDs), hepatocellular carcinoma (HCC), and liver injury, and several PTPs are being studied as drug therapeutic targets. Therefore, given the regulatory role of PTPs in diverse liver diseases, a collated review of their function and mechanism is necessary. Moreover, based on the current research status of targeted therapy, we emphasize the inclusion of several PTP members that are clinically significant in the development and progression of liver diseases. As an emerging breakthrough direction in the treatment of liver diseases, this review summarizes the research status of PTP-targeting compounds in liver diseases to illustrate their potential in clinical treatment. Overall, this review aims to support the development of novel PTP-based treatment pathways for liver diseases.

Abstract Circular RNA (circRNA) is thought to mediate the occurrence and development of human cancer and usually acts as a tiny RNA (miRNA) sponge to regulate downstream gene expression. However, it is not clear whether and how circACVR2A (hsa_circ_0001073) is involved in the progression of HCC. The purpose of this study is to clarify the potential role and molecular mechanism of circACVR2A in regulating the progression of hepatocellular carcinoma cells (HCC). The abundance of related proteins in circACVR2A, microRNA (miR511-5p) and PI3K-Akt signaling pathway was determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or Western blotting. Cell viability, invasion and apoptosis were analyzed by CCK-8, Transwell analysis and Tunel staining, respectively. The interaction between circACVR2A and microRNA was evaluated by double luciferase reporter gene assay. The results showed that circACVR2A was highly expressed in hepatocellular carcinoma cell lines. Our in vivo and in vitro data showed that circACVR2A promoted the proliferation, migration and invasion of HCC. In terms of mechanism, we found that circACVR2A can directly interact with miR511-5p and act as a miRNA sponge to regulate the expression of related proteins in PI3K-Akt signaling pathway. In HCC, circACVR2A can mediate miR-511-5p/mRNA network to activate PI3K signal pathway. This shows that the molecular regulatory network with circACVR2A as the core is a new potential target for diagnosis and treatment of hepatocellular carcinoma.

Abstract Background Hepatocellular carcinoma (HCC) constitutes an important contributor to fatalities. Coronavirus disease 2019 (COVID-19) frequently presents with complications such as respiratory distress, systemic inflammatory responses, and damage to various organs. Several studies have investigated the relationship between COVID-19 and mortality in patients with liver cancer, but there are few research on the relationship between them. This study is to explore the correlation between the two diseases and drugs treating them. Methods The Gene Expression Omnibus (GEO) database provides gene datasets of COVID-19 patients and HCC patients. Through differential gene analysis and weighted gene co-expression network analysis, we determined 223 genes represented in HCC and COVID-19. We then used functional annotation, protein–protein interaction network construction, predictive model development and verification, prognostic value analysis, and miRNA–gene network construction. Besides, we created a drug–hub–gene network by predicting possible medications that interact with hub genes using the Drug–Gene Interaction Database (DGIdb). Ultimately, we applied immunohistochemistry to ascertain the hub genes expression. Results This study revealed that eight core genes (RRM2, TPX2, DTL, CDT1, TYMS, CDCA5, CDC25C, and HJURP) co-existed in both HCC and COVID-19 and were differentially expressed in both HCC and normal tissues.CDC25C, RRM2, CDCA5, and HJURP had diagnostic value (AUC > 0.8) and prognostic value (adjusted P-value

Abstract Background Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. Methods MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. Results Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. Conclusion Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

Abstract Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy.

Abstract Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.

Abstract Hepatocellular Carcinoma (HCC) remains a leading cause of cancer deaths. Despite the rise of immunotherapies, many HCC patients don't benefit. There's a clear need for biomarkers to guide treatment decisions. This research aims to identify such biomarkers by combining radiological data and machine learning. We analyzed clinical and CT imaging data of 54 HCC patients undergoing immunotherapy. Radiologic features were examined to develop a model predicting short-term immunotherapy effects. We utilized 9 machine learning and 2 ensemble learning techniques using RapidMiner for model construction. We conducted the validation of the above feature combination using 29 HCC patients who received immunotherapy from another hospital, and tested and validated it using XGBoost combined with a genetic algorithm. In 54 HCC patients, radiomics features varied significantly between those with partial response (PR) and stable disease (SD). Key features in Gray Level Run Length Matrix (GLRLM) and in adjacent tissues' Intensity Direct, Neighborhood Gray Tone Difference Matrix (NGTDM), and Shape correlated with short-term immunotherapy efficacy. Selected feature combinations of 15, 19, and 8/15 features yielded better outcomes. Deep learning, random forest, and naive bayes outperformed other methods, with Bagging being more reliable than Adaboost. In the validation set of 29 HCC patients, the mentioned feature combination also demonstrated favorable performance. Furthermore, we achieved improved results when employing XGBoost in conjunction with a genetic algorithm for testing and validation. The machine learning model built with CT image features derived from GLCM, GLRLM, IntensityDirect, NGTDM, and Shape can accurately forecast the short-term efficacy of immunotherapy for HCC.

الملخص: أهداف البحث: قامت الدراسة بتقييم التأثير الوقائي المضاد لسرطان الكبد من المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز في الفئران الشبيهة بسرطان الكبد سي سي آي 4 / المستحثة بزيت الزيتون. طريقة البحث: تم تحضير المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز من الساق المجففة وجذور زانثوكسيلوم زانثوكسيلويدز بنسبة 1:1 وتميزت كيميائيا. تم توزيع ما مجموعه 30 من فئران ويستار الذكور الأصحاء (يتراوح وزنها بين 210-280 جم) بشكل عشوائي على ست مجموعات (التحكم، والنموذج، و العلاج الكيمائي المستخدم لعلاج السرطان كابيسيتابين، وجرعات المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز [50، 100، و200 ملغم/كغم]). تلقت جميعها، باستثناء المجموعة الضابطة، رباعي كلوريد الكربون/زيت الزيتون (3 مل/كجم، ص) في الصباح بينما في فترة ما بعد الظهر من نفس يوم الجرعة، تلقت المجموعة النموذجية محلول ملحي عادي (5 مل/كجم، ص)، ومجموعة كابيسيتابين (50 مجم/كجم). ومجموعات المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز(50 ، و 100، و 200 ملغم / كغم) مرة واحدة في الأسبوع لمدة 36 يوما. تم رصد معدل البقاء على قيد الحياة، والبروتين ألفا في الدم والبروتين سي التفاعلي. تم تقييم تشريح الكبد الإجمالي، وأنسجة الكبد، وإنزيمات الكبد، البيليروبين، الكرياتينين، اليوريا، الألبومين، الجلوبيولين، والمعلمات الدموية. النتائج: كان العائد من المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز 0,58%. تم اكتشاف قلويدات الفينانثريدين الرباعية في المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز. وكان معدل البقاء على قيد الحياة في فئران السيطرة 100٪ مقارنة مع الفئران في المجموعة النموذجية. أدى علاج المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز إلى تحسين معدل البقاء على قيد الحياة مقارنة بالمجموعة النموذجية. زادت مستويات مصل والبروتين ألفا في الدم وبروتين سي التفاعلي والبيليروبين في المجموعة النموذجية مقارنة بالمجموعة الضابطة. انخفض المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز في المصل والبروتين ألفا في الدم وبروتين سي التفاعلي والبيليروبين مقارنة بالنموذج. زاد مستوى انزيمات الكبد في المجموعة النموذجية مقارنة بالمجموعة الضابطة ولكن انخفض في المجموعة المعالجة بالمستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز. الاستنتاجات: أظهر المستخلص القلوي الجذعي والجذري المشترك لزانثوكسيلوم زانثوكسيلويدز تأثيرا وقائيا مضادا لسرطان الكبد ضد الأنماط الظاهرية المشابهة لسرطان الكبد سي سي آي 4 / زيت الزيتون في الجرذان. يسلط هذا الاكتشاف الضوء على إمكانات القلويدات الخام من زانثوكسيلوم زانثوكسيلويدز كقوالب طبيعية للتوليف شبه العلاجي المضاد لسرطان الكبد. Abstract: Objective: This study assessed the prophylactic anti-HCC effects of a combined stem and root alkaloidal extract of Zanthoxylum zanthoxyloides (Z. zanthoxyloides) (SRAEZZ) in rats with a CCl4/olive oil-induced HCC-like phenotype. Methods: SRAEZZ was prepared from dried stems and roots of Z. zanthoxyloides in a 1:1 proportion and chemically characterized. A total of 30 healthy male Wistar rats (weighing 210–280 g) were randomly assigned to six groups (control, model, capecitabine, and SRAEZZ [50, 100, or 200 mg/kg]). All groups except the control received CCl4/olive oil (3 mL/kg, po) in the morning, whereas in the afternoon of the same dosing day, the model group received normal saline (5 mL/kg, po), the capecitabine group received capecitabine (50 mg/kg, po), and the SRAEZZ groups received SRAEZZ (50, 100, or 200 mg/kg, po, respectively) once per week for 36 days. Survival rate, serum α-fetoprotein (AFP), and C-reactive protein (CRP) were monitored. Gross liver anatomy, liver histology, liver enzymes (ALP, AST, and ALT), bilirubin, creatinine, urea, albumin, globulins, and hematological parameters were assessed. Results: SRAEZZ yield was 0.58% from the initial stem and root sample (520 g). Quaternary phenanthridin alkaloids were detected in SRAEZZ. Control rats had a 100% survival rate compared with rats in the model group. SRAEZZ treatment improved the survival rate with respect to that in the model group. Serum AFP, CRP, and bilirubin levels were greater in the model group than the control group. SRAEZZ decreased serum AFP, CRP, and bilirubin below the levels observed in the model group. ALP, AST, and AST were higher in the model group, but lower in SRAEZZ-treated group, than the control group. Conclusion: SRAEZZ demonstrated prophylactic anti-HCC effects against CCl4/olive oil-induced HCC-like phenotypes in rats. These findings highlight the potential of crude alkaloids from Z. zanthoxyloides as natural templates for semi-synthesis of anti-HCC pharmacotherapeutics.

Abstract Purpose Hepatocellular carcinoma (HCC) is the most prevalent malignancies worldwide. Recently, oxidative phosphorylation (OXPHOS) has received extensive concern as an emerging target in antitumor therapy. However, the OXPHOS-involved underlying genes and clinical utilization in HCC remain worth exploring. The present research aimed to create an OXPHOS-relevant signature in HCC. Patients and methods In this study, the prognostic signature genes linked with OXPHOS were identified, and prognostic models were built using least absolute shrinkage and selection operator (LASSO) cox regression analysis. Furthermore, the combination study of immune microenvironment and signature genes looked into the involvement of immune cells in signature-based genes in HCC. Following that, chemotherapeutic drug sensitivity and immunotherapy analysis was implemented to predict clinical efficacy in HCC patients. Finally, clinical samples were collected to measure the expression of OXPHOS-related signature genes. Results Following a series of screens, six prognostic signature genes related with OXPHOS were identified: MRPS23, MPV17, MAPK3, IGF2BP2, CDK5, and IDH2, on which a risk model was built. The findings revealed a significant drop in the survival rate of HCC patients as their risk score increased. Meanwhile, independent prognostic study demonstrated that the risk score could accurately identify HCC patients. Immuno-microenvironmental correlation research suggested that the prognostic characteristics could serve as a reference index for both immunotherapy and chemotherapy. Finally, RT-qPCR exhibited a trend in signature gene expression that was consistent with the results. Conclusion In this study, a total of six prognostic genes associated with OXPHOS were selected and a prognostic model was constructed, providing an essential reference for the study of OXPHOS in HCC.

Yiqi Xiong,1,&ast; Wenying Qiao,2,3,&ast; Tingting Mei,1,&ast; Kang Li,4 Ronghua Jin,2,3 Yonghong Zhang1 1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Changping Laboratory, Beijing, 102206, People’s Republic of China; 4Research center for biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong Zhang, Interventional therapy center for oncology; Beijing You’an Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai Street, Fengtai District, Beijing, Tel +86-13810108505, Email zhangyh@ccmu.edu.cn Ronghua Jin, National center for infectious diseases, Beijing Ditan Hospital, Capital Medical University, 8 Jingshundong Street, Chaoyang District, Beijing, Tel +86-13811611118, Email ronghuajin@ccmu.edu.cnPurpose: The aim of our study was to investigate the relationship between albumin-bilirubin (ALBI) grade and recurrence in patients who underwent TACE sequential ablation. We developed and validated a nomogram to predict low levels of ALBI patients’ recurrence.Patients and Methods: A total of 880 patients undergoing TACE combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were retrospectively enrolled, including 415 patients with L-ALBI (≤-2.6) and 465 patients with high levels (>-2.6) of ALBI (H-ALBI). L-ALBI patients were randomized in a 7:3 ratio into the training cohort (N=289) and validation cohort (N=126). Multivariate Cox regression followed by random survival forest was carried out to identify independent risk factors for prediction nomogram construction. An examination of nomogram accuracy was performed using the C-index, receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) curves. According to the nomogram, the patients were divided into low-risk, intermediate-risk, and high-risk groups. Kaplan-Meier (KM) curves were applied to compare the difference in recurrence-free survival (RFS) among the three groups.Results: The median RFS in L-ALBI patients was significantly longer than the H-ALBI patients (40.8m vs 20.1m, HR:1.71, 95% CI:1.44– 2.04, P< 0.0001). The nomogram was composed of five variables, such as age, Barcelona Clinic Liver Cancer (BCLC) stage, globulin, gamma-glutamyl transferase to lymphocyte ratio (GLR), and international normalized ratio (INR). The C-index (0.722 and 0.731) and 1-, 3-, and 5-year AUCs (0.725, 0.803, 0.870, and 0.764, 0.816, 0.798) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves demonstrated good consistency and good clinical utility. There were significant differences in RFS between the low-risk, intermediate-risk, and high-risk groups (P< 0.0001).Conclusion: L-ALBI Patients who underwent TACE combined ablation had better recurrence-free survival than patients with H-ALBI. The nomogram developed and validated in our study had good predictive ability in recurrence for L-ALBI patients.Keywords: hepatocellular carcinoma, HCC, ablation, nomogram, recurrence, albumin-bilirubin, ALBI

Abstract Background HCC (Hepatocellular carcinoma) is the most common primary malignant cancer in the liver. Treatment options to incurable HCC such as sorafenib, an oral multikinase inhibitor, had numerous side effects and questionable effectiveness. Neurokinin-1 receptor (NK1R) have a major role in inflammation and tumour environment including the resistance to cell death, the induction of angiogenesis and the promotion of cell migration and proliferation. Additionally, NK-1R is over-expressed in human tumour cells including HCC. Moreover, Aprepitant, one of the NK-1R antagonists exerts multiple antitumor activities (antiproliferative, apoptotic, antimigration, and antiangiogenesis) in vivo and in vitro. Study aim To analyze the effectiveness of combining sorafenib with aprepitant in the management of HCC (experimental). Patients and methods In this retrospective experimental study, the human HCC cell line, HepG2, cells were exposed to increasing concentrations of sorafenib alone, aprepitant alone and combination of both sorafenib and aprepitant evaluation of cytotoxicity, apoptosis, MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK were done. Moreover, The extent of the NK-1 receptor expression was assessed by immunocytochemistry on 50 HCC paraffin blocks of Egyptian HCC patients and another 50 paraffin blocks of liver cirrhosis only as a control. Results Decreased levels of MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK was more substantial in the combination therapy compared to sorafenib alone and aprepitant alone. Moreover, the rate of apoptosis and cytotoxicity were significantly higher in the combination treatment group than the monotherapy groups with more anti inflammatory, anti angiogentic and anti metastatic effects. Also, among the 50 HCC paraffin blocks, the majority (60%) showed a strong NK-1 expression; which significantly (p < 0.05) correlated with the progression free survival (PFS) but not the overall survival (OS) of the patients when applying multivariate analysis. Conclusion HCC had strong expression and immunostaining for NK1R.Therefore, combined aprepitant and sorafenib may be a promising approach in HCC treatment compared to each one alone.

Abstract Background Emerging evidence indicates the pivotal involvement of circular RNAs (circRNAs) in cancer initiation and progression. Understanding the functions and underlying mechanisms of circRNAs in tumor development holds promise for uncovering novel diagnostic indicators and therapeutic targets. In this study, our focus was to elucidate the function and regulatory mechanism of hsa-circ-0003764 in hepatocellular carcinoma (HCC). Methods A newly discovered hsa-circ-0003764 (circPTPN12) was identified from the circbase database. QRT-PCR analysis was utilized to assess the expression levels of hsa-circ-0003764 in both HCC tissues and cells. We conducted in vitro and in vivo experiments to examine the impact of circPTPN12 on the proliferation and apoptosis of HCC cells. Additionally, RNA-sequencing, RNA immunoprecipitation, biotin-coupled probe pull-down assays, and FISH were employed to confirm and establish the relationship between hsa-circ-0003764, PDLIM2, OTUD6B, P65, and ESRP1. Results In HCC, the downregulation of circPTPN12 was associated with an unfavorable prognosis. CircPTPN12 exhibited suppressive effects on the proliferation of HCC cells both in vitro and in vivo. Mechanistically, RNA sequencing assays unveiled the NF-κB signaling pathway as a targeted pathway of circPTPN12. Functionally, circPTPN12 was found to interact with the PDZ domain of PDLIM2, facilitating the ubiquitination of P65. Furthermore, circPTPN12 bolstered the assembly of the PDLIM2/OTUD6B complex by promoting the deubiquitination of PDLIM2. ESRP1 was identified to bind to pre-PTPN12, thereby fostering the generation of circPTPN12. Conclusions Collectively, our findings indicate the involvement of circPTPN12 in modulating PDLIM2 function, influencing HCC progression. The identified ESRP1/circPTPN12/PDLIM2/NF-κB axis shows promise as a novel therapeutic target in the context of HCC. Graphical Abstract

Abstract Background Globally, HCC presents a significant health burden, characterized by high incidence and mortality rates. Epidemiological studies have increasingly suggested a link between dietary patterns and the risk of hepatocellular carcinoma (HCC), yet consensus on this relationship remains elusive. Objective This study aims to synthesize existing literature and provide a comprehensive analysis of the association between dietary patterns and HCC risk through meta-analytical methods. Methods A systematic search of PubMed, Embase, and the Cochrane Library databases was conducted to identify studies examining common dietary patterns in relation to HCC, published up to August 2023. Study quality was rigorously evaluated using the Newcastle–Ottawa Scale. We employed a random effects model to synthesize effect sizes, calculating hazard ratios (HRs) and 95% confidence intervals (CIs). Results We identified 13 papers, of these 10 investigating a priori dietary patterns(index-based dietary patterns) and 3 focusing on a posterior dietary patterns (data-driven dietary patterns). Analysis of a priori dietary patterns revealed that higher scores in the Healthy Eating Index (HEI) & alternative HEI (HR = 0.67, 95% CI: 0.54–0.85), Dietary Approaches to Stop Hypertension (DASH) (HR = 0.77, 95% CI: 0.66–0.91), and the Mediterranean diet (HR = 0.65, 95% CI: 0.56–0.75) were associated with a reduced risk of HCC. Conversely, pro-inflammatory dietary patterns were linked with an increased risk (HR = 2.21, 95% CI: 1.58–3.09). In a posterior dietary patterns, a vegetable-based diet was negatively correlated with HCC risk (HR = 0.63, 95% CI: 0.49–0.81). Conclusion This meta-analysis underscores a significant association between dietary patterns and the risk of HCC. Adherence to healthy dietary patterns characterized by high in vegetables, whole grains, legumes, nuts, and low in red and processed meats may confer a protective effect against HCC, whereas inflammatory diets appear to elevate risk.

Abstract Recent studies indicate that Glypican 1 (GPC-1) is aberrantly expressed and plays a key role in certain cancers, but little is known in the hepatocellular carcinoma. Raw data from TCGA, GTEx and TIMER databases were utilized to comprehensively analyze GPC-1 expression landscape in pan-cancer, and the biological function of GPC-1 was investigated in liver cancer cells. The results revealed that GPC-1 is highly expressed in HCC, negatively correlated with survival, and also positively correlated with immune infiltration and clinical stage. Furthermore, GPC-1 promoted cell proliferation and inhibited apoptosis in the HCC cell lines. WGCNA analysis and HCCDB database revealed that Akt acted as a key molecule related to GPC-1, influencing biological functions and regulating cell malignant behaviors via the AKT signaling pathway. In conclusion, our findings provide a relatively comprehensive understanding of the oncogenic role of GPC-1 in HCC, implying that GPC-1 could serve as an innovative therapeutic target.

Abstract RNA-binding proteins (RBPs) are a class of proteins that primarily function by interacting with different types of RNAs and play a critical role in regulating the transcription and translation of cancer-related genes. However, their role in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed RNA sequencing data and the corresponding clinical information of patients with HCC to screen for prognostic RBPs. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was identified as an independent prognostic factor for liver cancer. It is upregulated in HCC and is associated with a poor prognosis. Elevated IGF2BP3 expression was validated via immunohistochemical analysis using a tissue microarray of patients with HCC. IGF2BP3 knockdown inhibited the proliferation of Hep3B and HepG2 cells, whereas IGF2BP3 overexpression promoted the expansion of HuH-7 and MHCC97H cells. Mechanistically, IGF2BP3 modulates cell proliferation by regulating E2F1 expression. DNA hypomethylation of the IGF2BP3 gene may increase the expression of IGF2BP3, thereby enhancing cell proliferation in HCC. Therefore, IGF2BP3 may act as a novel prognostic biomarker and a potential therapeutic target for HCC.

Hepatitis C virus (HCV) infection is one of the major etiologies of hepatocellular carcinoma (HCC) with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in chronic hepatitis C (CHC) patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the direct-acting antiviral (DAA) era and might be due to preexisting inflammatory and fibrotic liver backgrounds, immune dysregulation between host and virus interactions, as well as host epigenetic scars, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors, and HCC surveillance strategy for HCC development after HCV eradication in CHC patients.

Abstract Although circular RNAs (circRNA) have been demonstrated to modulate tumor initiation and progression, their roles in the proliferation of hepatocellular carcinoma (HCC) are still poorly understood. Based on the analysis of GEO data (GSE12174), hsa-circRNA-0015004 (circ-0015004) was screened and validated in 80 sets of HCC specimens. Subcellular fractionation analysis was designed to determine the cellular location of circ-0015004. Colony formation and cell counting kit-8 were performed to investigate the role of circ-0015004 in HCC. Dual-luciferase reporter gene assays, RNA immunoprecipitation and chromatin immunoprecipitation were employed to verify the interaction among circ-0015004, miR-330-3p and regulator of chromatin condensation 2 (RCC2). The expression level of circ-0015004 was significantly upregulated in HCC cell lines and HCC tissues. HCC patients with higher circ-0015004 levels displayed shorter overall survival, and higher tumor size and TNM stage. Moreover, knockdown of circ-0015004 significantly reduced HCC cell proliferation in vitro and inhibited the growth of HCC in nude mice. Mechanistic studies revealed that circ-0015004 could upregulate the expression of RCC2 by sponging miR-330-3p, thereby promoting HCC cell proliferation. Furthermore, we identified that Ying Yang 1 (YY1) could function as an important regulator of circ-0015004 transcription. This study systematically demonstrated the novel regulatory signaling of circ-0015004/miR-330-3p/RCC2 axis in promoting HCC progression, providing insight into HCC diagnosis and treatment from bench to clinic.

Abstract Background The escalating prevalence of metabolic diseases has led to a rapid increase in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (NASH-HCC). While oxaliplatin (OXA)-based hepatic arterial infusion chemotherapy (HAIC) has shown promise in advanced-stage HCC patients, its efficacy in NASH-HCC remains uncertain. This study aims to assess the effectiveness of OXA-based HAIC and elucidate the mechanisms underlying OXA resistance in NASH-HCC. Methods The key lncRNAs were screened through RNA-seq analysis of NASH/non-NASH and OXA-sensitive/OXA-resistant (OXA-S/R) HCC tissues. The biological functions of the lnc-OXAR (OXA resistance–related lncRNA in NASH-HCC) in NASH-HCC were verified through a series of in vitro and in vivo experiments. The molecular mechanism of lnc-OXAR was elucidated by fluorescence in situ hybridization, immunoprecipitation-mass spectrometry (FISH), Immunoprecipitation-Mass Spectrometry (IP-MS), RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and a dual-luciferase reporter assay. Results NASH-HCC exhibited reduced responsiveness to OXA-based HAIC compared to non-NASH HCC. We identified and validated a novel transcript namedlnc-OXAR, which played a crucial role in conferring OXA resistance to NASH-HCC. Inhibition of lnc-OXAR suppressed HCC cell growth and restored OXA sensitivity both in NASH-HCC mouse models and in vitro. Mechanistically, lnc-OXAR recruited Ku70 and cystatin A (CSTA), preventing Ku70 degradation and facilitating DNA double-strand break (DSB) repair, thereby promoting OXA resistance in NASH-HCC. Additionally, WTAP-mediated m6A modification enhanced the stability of lnc-OXAR in an IGF2BP2-dependent manner. Notably, silencing lnc-OXAR significantly enhanced the response to OXA in patient-derived xenograft (PDX) models derived from NASH-HCC. Conclusions The reduced responsiveness of NASH-HCC to OXA treatment can be attributed to the upregulation of lnc-OXAR. Our findings provide a rationale for stratifying HCC patients undergoing OXA-based HAIC based on etiology. Lnc-OXAR holds promise as a novel target for overcoming OXA resistance in NASH-HCC and improving prognosis.

Qi-Feng Chen,1,&ast; Xiong-Ying Jiang,1,2,&ast; Yue Hu,1,&ast; Song Chen,1 Jun-Zhe Yi,1 Sui-Xing Zhong,1 Jiong-Liang Wang,1 Ning Lyu,1 Ming Zhao1 1Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510210, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Zhao, Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +862087343272, Email zhaoming@mail.sysu.edu.cnPurpose: The combination of sorafenib and hepatic arterial infusion chemotherapy (SoHAIC) has shown to enhance overall survival rates in patients with advanced hepatocellular carcinoma and major portal vein tumor thrombosis (HCC-Vp3-4) compared to sorafenib alone. Our objective was to evaluate the cost-effectiveness of SoHAIC versus sorafenib for the treatment of HCC-Vp3-4, taking into account the viewpoint of Chinese healthcare payers.Methods: This pharmacoeconomic study employed a Markov model to assess the cost-effectiveness of treating HCC-Vp3-4 with SoHAIC in comparison to sorafenib. The patient characteristics were drawn from individuals from the trial conducted between June 2017 and November 2019, with cost and health value data sourced from published literature. The primary outcome measure in this research was the incremental cost-effectiveness ratio (ICER), which indicates the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold per QALY was set at &dollar;30,492.00. Furthermore, 1-way sensitivity and probabilistic sensitivity analyses were carried out to validate the consistency of the results.Results: In the baseline scenario, sorafenib resulted in 0.42 QALY at a cost of &dollar;10,507.89, while SoHAIC generated 1.66 QALY at a cost of &dollar;32,971.56. When comparing SoHAIC to sorafenib, the ICER was &dollar;18,237.20 per QALY, which was below the WTP threshold per QALY. Furthermore, the 1-way sensitivity analysis demonstrated that the ICER remained within the WTP threshold despite fluctuations in variables. In the probabilistic sensitivity analysis, SoHAIC had a 98.8% probability of being cost-effective at the WTP threshold, considering a wide range of parameters.Conclusion: In this cost-effectiveness evaluation, SoHAIC demonstrated cost-effectiveness over sorafenib for HCC with major portal vein tumor thrombosis, as observed from the perspective of a Chinese payer.Keywords: HCC, portal vein tumor thrombosis, sorafenib, HAIC, Cost-effectiveness

Abstract Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

Objective To explore whether CYP2C9 is involved in the occurrence and development of hepatocellular carcinoma (HCC) and its function in the migration, invasion and proliferation of HCC cells.Methods The transcriptome data of HCC were retrieved from the TCGA database to analyze the expression of CYP2C9 and role of CYP2C9 in the prognosis of HCC; Constructing stable CYP2C9 overexpression cell lines of HepG2 and MHCC97H, detecting the effects of CYP2C9 overexpression on the migration, invasion and epithelial mesenchymal transition (EMT) process of HCC cells through Transwell migration assay, Transwell invasion assay, and Western Blot assay, respectively; The effect of CYP2C9 overexpression on the proliferation ability of HCC cells was detected through CCK-8 assay, colony formation assay, and Western Blot assay.Results Bioinformatics analysis showed that the expression of CYP2C9 was significantly downregulated in HCC , and the expression of CYP2C9 was positively correlated with the clinical prognosis of HCC patients; The results of cellular and molecular experiments showed that CYP2C9 overexpression significantly inhibited the migration, invasion and EMT process of HepG2 and MHCC97H cells, whereas had no significant effect on cell proliferation.Conclusion CYP2C9 may affect the progression of HCC by inhibiting the migration, invasion, and EMT processes of HCC cells.

Chuang Qin,1 Xiaofei Ye,1 Hongliang Luo,1 Hu Jin,1 Qiang Liu,1 Jiangfa Li2 1Hepatobiliary Surgery, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi, People’s Republic of China; 2Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, Guilin City, Guangxi, People’s Republic of ChinaCorrespondence: Jiangfa Li, Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, No. 15, Lequn Road,Xiufeng District, Guilin City, Guangxi, 541001, People’s Republic of China, Email ljf.126@qq.comPurpose: This study contributes to the evolving understanding of the pivotal involvement of Sirtuins (SIRTs) in various human cancers, with a particular focus on elucidating their expression patterns and clinical relevance within the context of hepatocellular carcinoma (HCC). The investigation involves a comprehensive analysis of mRNA expression and prognostic implications associated with distinct SIRTs in HCC.Patients and Methods: Initial data pertaining to SIRT expression in HCC patients were collated from publicly accessible databases. Subsequently, the expression levels of select members of the SIRT family were validated using clinicopathological specimens from HCC patients. Additionally, HCC tissue microarray was employed to scrutinize the correlation between SIRT7 expression and HCC prognosis.Results: The findings indicated a substantial upregulation of SIRT2, SIRT3, SIRT4, SIRT6, and SIRT7 in HCC tissues. Survival analysis underscored a pronounced association between elevated mRNA levels of SIRT3, SIRT6, and SIRT7 and an adverse prognosis for HCC patients. Particularly, SIRT7 emerged as a potential independent risk factor for poor prognosis in HCC patients. Examination of the HCC tissue microarray revealed heightened expression of SIRT7 in 68 cases (54.8%) of HCC tissues. Multivariate analysis established high SIRT7 expression as an independent risk factor for diminished Disease-Free Survival (DFS) and Overall Survival (OS) in HCC patients.Conclusion: The aberrant expression of SIRT7 presents itself may be as a novel biomarker for predicting the prognosis of HCC patients.Keywords: HCC, microarray, prognosis, SIRT7, survivor