Liver Hepatocellular Carcinoma Research Articles

What is the role of nonalcoholic fatty liver disease in pulmonary carcinoma development?

This article summarizes the epidemiological characteristics and clinical manifestations of nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD has been increased dramatically and become the leading cause of chronic liver disease worldwide. In addition to its adverse outcomes of liver fibrosis, cirrhosis, and hepatocellular carcinoma, and related complications, NAFLD has recently been found to be associated with the high-risk extrahepatic carcinomas, such as various types of lung cancer (i.e ., lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer). The presence of hepatic steatosis also predisposes lung cancer to liver metastasis, but has better response to immune checkpoint inhibitors. Whether other factors (i.e ., gender, smoking, etc .) are associated with NAFLD and lung cancer remains controversial. We also comment on the reciprocal relationships between NAFLD and components of metabolic syndrome. Most metabolic syndrome components are suggested to facilitate lung cancer development via activating insulin/insulin-like growth factor axis. In addition, suppressed anti-tumor immunity and accelerated tumor progression could be attributed to the cell-specific metabolic reprogramming in condition of high-fat diet and related obesity. These findings may reveal the role of NAFLD in pulmonary carcinoma and help develop new treatment strategies for this disease.

Local control and recurrence patterns after stereotactic irradiation delivered in more than 4 fractions for hepatocellular carcinomas and liver metastases: a retrospective study

BackgroundStereotactic Body Radiation Therapy (SBRT) is a safe and effective treatment for liver metastases or hepatocellular carcinoma (HCC) with a dose–response relationship for local control (LC). Proximity to organs at risk (OAR) often requires dose de-escalation. This study evaluated LC and recurrence patterns in patients administered hepatic SBRT in more than 4 fractions due to dosimetric constraints.MethodsThis retrospective study included 33 patients treated with SBRT (Cyberknife®) in more than 4 fractions for HCC or liver metastases, between January 2011 and December 2019. Patients were ineligible for treatment in 3 or 4 fractions due to OAR proximity. Recurrence patterns were analysed according to the volume shared between recurrence and initial target or treatment isodose volumes.ResultsThe primary dose ranged from 35 to 50 Gy delivered in 5 to 7 fractions for the treatment of HCC (39%) or liver metastases (61%) mainly secondary to colorectal cancer (40%).LC rate was 64%, with 12 patients showing recurrence volume overlap with the initial target volume or treatment isodose. In-field recurrence occurred in only 12.5% of patients with most relapses being out-of-field. No grade ≥ 3 events were reported.ConclusionDespite dose reductions to spare OAR, SBRT showed satisfactory LC with low toxicity. Out-of-field recurrence remains the most common pattern identified and likely related to underlying disease. Prospective data are necessary to determine whether preserving dose while reducing planning target volume (PTV) coverage could enhance LC.Trial registrationAll patients were retrospectively registered, and this study is registered at the Health Data Hub site (number HDH414).

Dose-Dependent PFESA-BP2 Exposure Increases Risk of Liver Toxicity and Hepatocellular Carcinoma

Per- and polyfluoroalkyl substances (PFASs) are persistent and highly bioaccumulative emerging environmental contaminants of concern that display significant toxic and carcinogenic effects. An emerging PFAS is PFESA-BP2, a polyfluoroalkyl ether sulfonic acid found in drinking water and the serum of humans and animals. While PFESA-BP2-induced liver and intestinal toxicity has been demonstrated, the toxicological mechanisms and carcinogenic potential of PFESA-BP2 have remained relatively understudied. Here, we studied how different doses of PFESA-BP2 affect gene activity related to liver toxicity and the risk of liver cancer such as hepatocellular carcinoma (HCC) in mice exposed to PFESA-BP2 once daily through oral gavage for seven days. An analysis of key hepatic pathways suggested increased risk of hepatotoxicity as a result of PFESA-BP2 exposure. Increased oxidative stress response was associated with all concentrations of exposure. Liver toxicity pathways, including PXR/RXR activation and hepatic fibrosis, showed dose-dependent alteration with activation primarily at low doses, suggesting an increased risk of hepatic inflammation and injury. Additionally, an analysis of carcinogenic and HCC-specific pathways suggested PFESA-BP2-induced risk of liver cancer, particularly at low doses. Low-dose PFESA-BP2 exposure (0.03 and 0.3 mg/kg-day) was associated with an increased risk of HCC carcinogenesis, as indicated by the activation of tumor-related and HCC-associated pathways. In contrast, these pathways were inhibited at high doses (3.0 and 6.0 mg/kg-day), accompanied by the activation of HCC-suppressive pathways. The increased risk of HCC development at low doses was mechanistically linked to the activation of signaling pathways such as HIF, EGF, NOTCH4, HGF, and VEGF. Biomarkers linked to liver cancer risk, prognoses, and diagnoses were also identified as a result of exposure. Overall, our findings on liver carcinogenic and hepatotoxic pathway activation patterns suggest that PFESA-BP2 increases the risk of liver toxicity and HCC development, particularly at low doses.

Integrative analysis disclosing UQCRC1 as a potential prognostic and immunological biomarker of lung adenocarcinoma.

Lung cancer is one of the most malignant cancers in the world. Approximately 40 % of lung cancer cases are lung adenocarcinoma (LUAD). Exploring new biomarkers was an urgent need for treatments of LUAD. Here, we aimed to perform a pan-cancer analysis of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) and verify it in LUAD. Compared to normal samples, we observed that UQCRC1 was significantly enhanced in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), LUAD, liver hepatocellular carcinoma (LIHC), and several other cancers. In terms of overall survival, UQCRC1 was positively associated with poor prognosis of LUAD and skin cutaneous melanoma (SKCM). Almost more than 8 % deeply deleted frequency of UQCRC1 was showed in lymphoid neoplasm diffuse large B-cell lymphoma (DLBC). In LUAD, SKCM, and a few cancers, UQCRC1 was negatively correlated with the infiltration of B cells and cancer-associated fibroblasts. As regards further mechanism analysis, we found that UQCRC1 modulated cancer progression via mitochondrial related metabolism and oxidative phosphorylation. Taking advantage of the Kras-driven spontaneous LUAD mice model, online single-cell data, and clinical tissues, we particularly confirmed that UQCRC1 was highly expressed in LUAD and acted as a prognostic marker for LUAD. These findings implied that UQCRC1 played an important role in cancers, especially in LUAD.

MIF/CD74 axis in hepatic stellate cells mediates HBV-related liver fibrosis.

Chronic hepatitis B virus (HBV) infection is a major risk factor for liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Despite advances in understanding HBV-related liver diseases, effective therapeutic strategies remain limited. Macrophage migration inhibitory factor (MIF) has been implicated in various inflammatory and fibrotic conditions, but its role in HBV-induced liver fibrosis has not been fully explored. This study investigates the involvement of MIF in liver fibrosis and evaluates its potential as a therapeutic target. We found that MIF expression was significantly elevated in hepatic stellate cells (HSCs) following stimulation with HBVcc (HBV cell culture) or HBV surface antigen (HBsAg). Through its receptor CD74, MIF enhanced the TGF-β/SMAD signaling pathway, promoting HSC activation and liver fibrosis progression. Histological analysis revealed higher MIF and CD74 expression in HBsAg-positive individuals compared to HBsAg-negative controls. Moreover, MIF expression correlated with the activation of fibrosis markers, including α-SMA and TGF-β-related proteins. Inhibition of MIF with the specific inhibitor ISO-1 attenuated fibrosis progression, suggesting that targeting MIF could offer a promising approach for treating HBV-related liver fibrosis. Our findings underscore the critical role of the MIF/CD74 axis in liver fibrosis and provide a basis for future therapeutic strategies targeting MIF in chronic liver diseases.

End-of-life (EOL) outcomes and healthcare utilization for patients with hepatocellular carcinoma (HCC) who received immune checkpoint inhibition (ICI).

560 Background: ICI is standard of care treatment for advanced HCC. EOL outcomes for patients with HCC who receive ICI prior to death are unknown. We examine relationships between EOL outcomes, healthcare utilization, and receipt of ICI for patients with advanced HCC referred to our tertiary center. Methods: Patients with advanced HCC evaluated at our center on or after January 1, 2020 and who died by March 29, 2024 were included. Patients were identified using diagnostic codes for liver cancer and HCC, and subsequently verified by manual review of the electronic health record. Demographic data, Child-Pugh (CP) status, and treatment history were collected. Primary EOL outcomes include: documentation of advance directives and goals of care (GOC) conversations, location of death, palliative care referral, hospice referral, days in hospice, and code status. Secondary healthcare utilization outcomes include: systemic therapy receipt, emergency department (ED) visits, hospitalization, and intensive care unit (ICU) admissions within 14, 30, and 90 days of death. Outcomes were stratified by ICI or non-ICI as last therapy received and p-values were derived using Pearson’s chi-square test for equality of proportions. Results: Of 221 evaluated patients, 71 died and met criteria for analysis. Baseline characteristics include mean age 64.1 years, 70.8% male, 71.8% received systemic treatment (median 1 line, range [1-7]), 54.1% CPA, 37.5% CPB, and 8.3% CPC at the time of last treatment. No statistically significant differences in primary EOL outcomes were detected when stratified by receipt of ICI or non-ICI as last therapy. Median days enrolled in hospice were not statistically significant between groups (24.5 days [non-ICI] vs 10 days [ICI]; p = 0.39). A higher proportion of patients who received ICI as last therapy had increased healthcare utilization across all outcomes (see Table). Conclusions: Patients with advanced HCC receiving ICI as their last treatment before death compared to those receiving non-ICI had similar EOL outcomes but higher healthcare utilization. This may be due to increased real-world use of ICI in CPB patients. Further investigation into risk stratification to predict high healthcare utilizers could guide decision-making and conversations around ongoing use of ICI, particularly near the EOL. Healthcare utilization outcomes stratified by receipt of ICI. Outcome Before Death n = 71 90 days 30 days 14 days Therapy within Total: Last therapy ICI 33/71 (46.5%)69.7% 18/71 (25.4%)66.7% 6/71 (8.5%)33.3% ED visit Total: Last therapy ICI 29/71 (40.8%)58.6% 27/71 (38.0%)55.6% 22/71 (30.1%)59.1% Hospitalization Total: Last therapy ICI 32/71 (45.1%)59.4% 30/71 (42.3%)56.6% 29/71 (40.8%)58.6% ICU admission Total: Last therapy ICI 6/71 (8.5%)66.7% 6/71 (8.5%)66.7% 6/71 (8.5%)66.7%

Parental Alcohol Use Disrupts Offspring Mitochondrial Activity, Promoting Susceptibility to Toxicant-Induced Liver Cancer.

The early onset and incidence of liver disease and hepatocellular carcinoma have doubled in the last two decades and are primarily attributed to an unhealthy lifestyle. However, emerging studies suggest that increases in these age-related pathologies may link to heritable alterations in the control of cellular bioenergetics induced by the parental environment. Because our preclinical studies examining the fetal offspring of alcohol-exposed males and females have consistently identified epigenetic alterations in mitochondrial activity, we hypothesized that chronic parental alcohol exposure programs an increased predisposition of offspring to develop liver disease and hepatocellular carcinoma induced by an environmental toxicant. Here, we employed a multiplex mouse model to compare the sensitivities of male offspring derived from maternal, paternal, and dual-parental alcohol exposures to the potent hepatocellular carcinoma inducer Diethylnitrosamine and determine their predisposition for tumor formation and growth. Our analysis reveals that parental alcohol exposures disrupt the activity of offspring mitochondrial complex I in the liver, promoting enduring oxidative stress and activating Transforming Growth Factor β signaling. This lasting imbalance correlates with increased Interleukin 6 production, promoting an inflammatory precancerous state. In male offspring, chronic parental alcohol consumption leads to increased tumor incidence, multiplicity, and size. Significantly, maternal and paternal alcohol use interact in driving the progression of toxicant-induced liver disease, with some adverse outcomes of dual-parental offspring exceeding those caused by either maternal or paternal alcohol use alone. We conclude that chronic parental alcohol use alters mitochondrial complex I activity and immune function, predisposing male offspring to a proinflammatory precancerous state.

Unveiling Hepatitis C: Causes, Impact and advances in treatment

Hepatitis C Virus (HCV) infection continues to pose a major global health issue, with around 58 million chronic cases reported worldwide and about 1.5 million new infections each year. This virus is a primary contributor to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC), leading to approximately 290,000 deaths annually (WHO, 2022). The introduction of direct-acting antiviral (DAA) therapies has transformed HCV treatment, with sustained virologic response (SVR) rates surpassing 95% across various genotypes. However, challenges remain in meeting the World Health Organization's target of eliminating HCV as a public health threat by 2030. Key obstacles include low diagnosis rates, as only 21% of those infected with HCV are aware of their condition, and restricted access to treatment, especially in low- and middle-income countries (LMICs). This article reviews the latest epidemiological trends related to HCV, focusing on the disparities in disease burden and access to healthcare. It discusses innovative diagnostic methods, such as point-of-care testing, and emphasizes the importance of universal screening programs in areas with high prevalence. Additionally, we look at new therapeutic strategies, including pan-genotypic DAAs and their effects on marginalized communities. Lastly, we examine public health initiatives aimed at enhancing HCV prevention, such as harm reduction programs and vaccination efforts for co-infections like hepatitis B. By integrating findings from recent studies and reports, this article highlights the necessity for collaborative global efforts to address the challenges of HCV elimination. Strategies that emphasize prevention, early detection, and fair access to treatment are crucial for alleviating the HCV disease burden and reaching elimination goals.

Seroprevalence and Risk Factors of Hepatitis B and C Viruses among Hemodialysis Patients in Mukalla City, Hadhramout, Yemen

Introduction: Hemodialysis (HD) patients are at high risk of infection with blood transfusion viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Chronic infections with HBV and HCV may lead to liver cirrhosis, hepatic failure and hepatocellular carcinoma. Objective: The present work was aimed to screen the seroprevalence rate and risk factors of HBV and HCV infections among HD patients attending the Artificial Kidney Center in Mukalla city, Hadhramout Governorate, Yemen. Methods: A cross-sectional analytical study conducted on 110 HD patients (73 males and 37 females) in the period from January to March 2024. Hepatitis B surface antigen (HBsAg) and anti-HCV were detected using the electrochemiluminescence (ECL) immunoassay technique. The data concerning risk factors were collected using a designed questionnaire and analyzed using the SPSS software. Results: In our study, 6(5.5%) of HD patients were HBsAg positive and 8(7.3%) were anti-HCV positive. There was statistically significant correlation between the age groups and educational level with the prevalence rate of HBV (P < 0.05). Analysis of other risk factors in HD patients with HBV and HCV infections of variables the blood transfusion during hemodialysis, previous operational surgery, number of hemodialysis more than 3 times per month, duration of hemodialysis 1-5 years, and unvaccinated patients against HBV don't showed any statistically significant associations. Conclusion: The present study showed a reduction in the prevalence of HBV and HCV infections in HD patients, but represents a serious community health problem to become a nosocomial infection in the Artificial Kidney Center in Mukalla city, Hadhramout. So, proper and effective procedures for infection control may be reduce and prevent viral hepatitis infections.

Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.

A novel ubiquitination-related gene signature for overall survival prediction in patients with liver hepatocellular carcinoma

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

Tristetraprolin Family Members and Processing Bodies: A Complex Regulatory Network Involved in Fatty Liver Disease, Viral Hepatitis and Hepatocellular Carcinoma

Chronic liver diseases, such as those encountered with obesity, chronic/abusive alcohol consumption or viral infections, represent not only major public health concerns with limited therapeutic options but also important risk factors for the onset of hepatocellular carcinoma (HCC). Deciphering the molecular traits underlying these disorders is of high interest for designing new and effective treatments. The tristetraprolin (TTP) family members are of particular importance given their ability to control the expression of a wide range of genes involved in metabolism, inflammation and carcinogenesis at the post-transcriptional level. This regulation can occur within small cytoplasmic granules, namely, processing bodies (P-bodies), where the mRNA degradation occurs. Increasing evidence indicates that TTP family members and P-bodies are involved in the development of chronic liver diseases and cancers. In this review, we discuss the role of this regulatory mechanism in metabolic-dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), hepatic viral infections and HCC.

Natural Compounds from Alhagi maurorum as Potential HCC and HepG2 Inhibitors: An Integrated Study using Pharmacophore Development, Molecular Docking, MD Simulation, and DFT Approaches.

The rise in the frequency of liver cancer all over the world makes it a prominent area of research in the discovery of new drugs or repurposing of existing drugs. This article describes the pharmacophore-based structure-activity relationship (3DQSAR) on the secondary metabolites of Alhagi maurorum to inhibit human liver cancer cell lines Hepatocellular carcinoma (HCC) and hepatoma G2 (HepG2) which represents the molecular level understanding for isolated phytochemicals of Alhagi maurorum. The definite features, such as hydrophobic regions, average shape, and active compounds' electrostatic patterns, were mapped to screen phytochemicals. The 3D-QSAR model generates pharmacophore-based descriptors and alignment of active compounds. Further, docking studies were performed on the active compounds to check out their binding affinity with the active site of the target proteins. It was further validated by applying molecular simulations, and the results were found to be accurate. The geometrical optimization and energy gap of the hit compound were calculated by the density functional theory (DFT). Then, ADMET was performed on this hit compound for drug-like features and toxicity. Out of 59 compounds, eight ligands were found active after the 3D-QSAR study. After that, molecular docking was performed on the active compounds F72, F52, F54, F29, F37, F38, F25, and F29, which were recognized as potential targets, and the docking results showed that compound F52 (also an FDA-approved drug) was the best hit. F52 was found to be the best hit against liver cancer cell lines HCC and HepG2. This study would be helpful for early drug discovery optimization and lead identification.

Lactulose use among patients with alcohol-related liver cirrhosis as a surrogate marker of hepatic encephalopathy: prevalence and association with mortality - a Danish nationwide cohort study

Background & aims: Hepatic encephalopathy (HE), one of the most serious prognostic factors for mortality in alcohol-related cirrhosis (ALD cirrhosis), is not recorded in Danish healthcare registries. However, treatment of HE with lactulose, the universal first-line treatment, can be identified through data on filled prescriptions. This study aimed to investigate if lactulose can be used as a surrogate marker of HE. Methods: We used Danish healthcare registries to establish a cohort of patients with ALD cirrhosis diagnosed in 2000–2018. Lactulose users were identified using data on filled prescriptions. We computed the prevalence and cumulative incidence of lactulose use, and then matched lactulose users with cohort members who were not using lactulose. This matched dataset was used to identify predictors of lactulose initiation, and to examine the association between lactulose use and all-cause mortality. Results: We included 23,089 patients, among whom we identified 4,789 first-time lactulose users. The prevalence of lactulose usage rose to 11% within the first 6 months after ALD diagnosis and reached 19% 5 years after inclusion. The 1-year cumulative incidence of lactulose use was 31%, and predictors of initiating lactulose use were history of severe liver disease (ascites, portal hypertension, spontaneous bacterial peritonitis or gastrointestinal bleeding) or hepatocellular carcinoma. Lactulose use was associated with higher mortality (adjusted hazard ratio 1.61 [95% confidence interval 1.53; 1.69]). Conclusions: Lactulose is used by 10–20% of patients with ALD cirrhosis, primarily those with severe cirrhosis, and lactulose users have a markedly higher mortality than nonusers. We conclude that lactulose use can be used to estimate the prevalence of HE and to reduce confounding from HE, but it should not be used as a surrogate for HE in studies with HE as an outcome.

Feasibility of indocyanine green fluorescence imaging to predict biliary complications in living donor liver transplantation: A pilot study.

Liver transplantation (LT) is now a critical, life-saving treatment for patients with liver cirrhosis or hepatocellular carcinoma. Despite its significant benefits, biliary complications (BCs) continue to be a major cause of postoperative morbidity. This study evaluates the fluorescence intensity (FI) of the common bile duct (CBD) utilizing near-infrared indocyanine green (ICG) imaging, and examines its association with the incidence of BCs within three months post-LT. This investigation analyzed data from nine living donor LT (LDLT) recipients who were administered 0.05 mg/kg of ICG prior to bile duct anastomosis. Real-time perfusion of the CBD was recorded for three minutes using an ICG camera, and FI was quantified using Image J (National Institutes of Health). Key parameters assessed included F max, F1/2 max, T1/2 max, and the slope (F max/T max) to evaluate the fluorescence response. BCs occurred in two out of nine patients. These two patients exhibited the longest T1/2 max values, which were linked with lower slope values, implicating a potential relationship between extended T1/2 max, reduced slope, and the occurrence of postoperative BCs. The study indicates that ICG fluorescence imaging may serve as an effective tool for assessing bile duct perfusion in LDLT patients. While the data suggest that an extended T1/2 max and lower slope may correlate with an increased risk of BCs, further validation through larger studies is required to confirm the predictive value of ICG fluorescence imaging in this setting.

Migrasome-related prognostic signature TSPAN4 correlates with immune infiltrates and metabolic disturbances in hepatocellular carcinoma.

We aim to comprehensively analyze and validate the prognostic efficacy of tetraspanin 4 (TSPAN4) and several other migrasome-related markers in hepatocellular carcinoma (HCC). The expression, diagnostic, and prognostic efficacy of five migrasome-related genes in HCC were analyzed using several databases. Five pairs of adjacent non-tumor tissues and HCC tissues were used to validate the expression. The prognostic efficacy of TSPAN4 was validated in a HCC cohort. TSPAN4 was knocked down in Huh-7 cells, EdU, and CCK-8, and wound healing assays were conducted to analyze its effects on cell proliferation and migration. In addition, transcriptomic sequencing was used to identify differentially expressed genes. Compared with those in normal tissues, four genes (TSPAN4, PIGK, NDST1, and CPQ) were elevated in liver hepatocellular carcinoma (LIHC), but not TSPAN7. Of these, only elevated TSPAN4 predicted unfavorable prognosis of HCC patients. The expression and prognostic efficacy of TSPAN4 were further confirmed in a HCC cohort (97 patients); and patients in the TSPAN4high group showed unfavorable overall survival (log-rank P = 0.0055). Functional analysis showed that TSPAN4 knockdown significantly suppressed cell migration, but not cell proliferation. Moreover, TSPAN4 knockdown induced disturbances of the metabolic pathways, mainly pentose and glucuronate interconversions. TPSAN4 is a promising prognostic and therapeutic target for HCC treatment and may be involved in the metabolic pathways that affect disease progression.

Investigating the Immunogenic Properties of a Mutagenized NS3/4A-Based HCV Genotype 3a DNA Vaccine.

Chronic hepatitis C virus (HCV) infection poses a major health risk worldwide, with patients susceptible to liver cirrhosis and hepatocellular carcinoma. This study focuses on the development of effective therapeutic strategies for HCV infection through the investigation of immunogenic properties of a DNA construct based on the NS3/4A gene of HCV genotype (g)3a. Gene expression of the mutagenized (mut) NS3/4A target genes was assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Additionally, bioinformatics tools were employed to evaluate the impact of the mut-NS3/4A-based DNA vaccine. Analysis revealed increased mut-NS3/4A mRNA levels and target protein abundance compared with the native sequence. Elevated mut-NS3/NS4A levels could result from increased RNA stability and proper protein folding. Physicochemical analyses of the protein demonstrated favorable attributes such as thermostability and solubility. Three-dimensional mut-NS3/4A protein modeling confirmed its high stability and agreement with known protein structures. Additionally, potential immunogenic regions of both T and B cell epitopes were discovered based on peptide binding to major histocompatibility complex molecules of Asian origin. Importantly, these epitopes exhibited nonallergenic and nontoxic characteristics. These findings highlight the potential of the NS3/4A-based DNA construct as a promising candidate for an HCVg3a vaccine tailored for the Asian population, providing valuable insights for future immunotherapeutic approaches.

Treatment of chronic hepatitis B: options, monitoring, special cases and adverse effects

Introduction: Hepatitis B remains a significant clinical issue. Despite the availability of effective vaccines, the world is still not free from this problem. Chronic hepatitis B virus (HBV) infection affects approximately 296 million people worldwide and is the leading cause of cirrhosis and liver cancer globally. HBV-related cirrhosis resulted in an estimated 331,000 deaths in 2019, and it is estimated that the number of deaths from HBV-related liver cancer in 2019 was 192,000, an increase from 156,000 in 2010. The rate of vaccination is particularly unsatisfactory in low-income countries, but even in high-income countries, the issue of hepatitis B has not been completely eradicated. Aim of the study: The aim of this paper is primarily to systematize knowledge regarding the natural course of HBV infection and therapeutic options for chronic hepatitis B, both in adults and children. It also aims to highlight the principles of monitoring pharmacotherapy. The paper also describes therapeutic possibilities in special cases, such as pregnancy, liver transplantation, and the initiation of immunosuppressive therapy. Attention is also given to the potential adverse effects of pharmacotherapy. Conclusions: As hepatitis B infection continues to pose a significant global health challenge and remains the leading cause of liver cirrhosis and hepatocellular carcinoma, it is essential to review the available treatment options for this condition. Even in Europe, where vaccination coverage has reached high levels, cases of hepatitis B are still detected, often incidentally. This review aims to provide an in-depth analysis of therapeutic approaches for chronic hepatitis B, considering factors such as patient age, clinical status, and liver fibrosis stage. Additionally, it emphasizes the importance of monitoring treatment efficacy and safety, while also addressing the potential adverse effects associated with antiviral therapy.

DECODING THE RISK PROFILE OF NON-ALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: This is a systematic review and meta-analysis that aims to evaluate the prevalence of non-alcoholic fatty liver disease (NAFLD) and the risk factors such as type 2 diabetes mellitus (T2DM), hypertension, obesity, PCOS, and sleep apnea associated with it. NAFLD is one of the most prevalent diseases that affect approximately 40% of diabetic, hypertensive, dyslipidemic obese individuals. Its asymptomatic nature often leads to under diagnosis and progress to severe liver cirrhosis and hepatocellular carcinoma. Methods: A total of 1819 studies from database from 2019 to 2024 were identified, finally 10 studies were selected, the Statistical Package for the Social Sciences software was used for data analysis. Results: The analyses across different geographic regions with 620,3969 patients with NAFLD, T2DM prevalence came out to be 15% among males, whereas 22.2% in females. A prevalence of 52.55% was noted in the obese population and 26.74% in lean individuals, with PCOS 43%, metabolic syndrome 75.3%, and sleep apnea 40% and various risk factors were also identified. Conclusion: This review throws light on the nature of NAFLD, focusing on the need for increased awareness and screening among people at risk, strategies could help avert liver disease progression.

Analysis and Validation of Tyrosine Metabolism-related Prognostic Features for Liver Hepatocellular Carcinoma Therapy.

To explore tyrosine metabolism-related characteristics in liver hepatocellular carcinoma (LIHC) and to establish a risk signature for the prognostic prediction of LIHC. Novel prognostic signatures contribute to the mining of novel biomarkers, which are essential for the construction of a precision medicine system for LIHC and the improvement of survival. Tyrosine metabolism plays a critical role in the initiation and development of LIHC. Based on the tyrosine metabolism-related characteristics in LIHC, this study developed a risk signature to improve the prognostic prediction of patients with LIHC. To investigate the correlation between tyrosine metabolism and progression of LIHC and to develop a tyrosine metabolism-related prognostic model. Gene expression and clinicopathological information of LIHC were obtained from The Cancer Genome Atlas (TCGA) database. Distinct subtypes of LIHC were classified by performing consensus cluster analysis on the tyrosine metabolism-related genes. Univariate and Lasso Cox regression were used to develop a RiskScore prognosis model. Kaplan-Meier (KM) survival analysis with log-rank test and area under the curve (AUC) of receiver operating characteristic (ROC) were employed in the prognostic evaluation and prediction validation. Immune infiltration, tyrosine metabolism score, and pathway enrichment were evaluated using single-sample gene set enrichment analysis (ssGSEA). Finally, a nomogram model was developed with the RiskScore and other clinicopathological features. Based on the tyrosine metabolism genes in the TCGA cohort, we identified 3 tyrosine metabolism-related subtypes showing significant prognostic differences. Four candidate genes selected from the common differentially expressed genes (DEGs) between the 3 subtypes were used to develop a RiskScore model, which could effectively divide LIHC patients into high- and lowrisk groups. In both the training and validation sets, high-risk patients tended to have worse overall survival, less active immunotherapy response, higher immune infiltration and clinical grade, and higher oxidative, fatty, and xenobiotic metabolism pathways. Multivariate analysis confirmed that the RiskScore was an independent indicator for the prognosis of LIHC. The results from pan-- cancer analysis also supported that the RiskScore had a strong prognostic performance in other cancers. The nomogram demonstrated that the RiskScore contributed the most to the prediction of LIHC prognosis. Our study developed a tyrosine metabolism-related risk model that performed well in survival prediction, showing the potential to serve as an independent prognostic predictor for LIHC treatment.