Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength.

This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria.

We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk.

HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.

Early job loss after curative treatment for hepatocellular carcinoma (HCC) is associated with significant socioeconomic and health challenges, potentially worsening patient outcomes.

To examine the impact of early job loss on all-cause mortality among HCC survivors following curative treatment.

We conducted a retrospective cohort study using Korean National Health Insurance Service data on 4578 HCC survivors (aged 35-54) with economic activity treated between 2009 and 2015. Primary and secondary outcomes were all-cause mortality and HCC recurrence, respectively. Early job loss was defined as a shift from insurer to dependent status. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multivariable Cox regression models, and subgroup analyses were performed. Causal mediation analysis assessed early HCC recurrence as a mediator between early job loss and all-cause mortality.

Among 4578 patients (median follow-up, 8.3 years), 1189 (26%) died including 989 (25%) in the job-maintained group and 200 (35%) in the early job loss group (P < .001). Early job loss was significantly associated with increased risk of all-cause mortality (adjusted HR 1.52 [95% CI 1.30-1.78]), but not with HCC recurrence (adjusted HR 1.07 [95% CI 0.91-1.25]). Subgroup analyses showed prominent association among middle-income level, non-liver cirrhosis, non-alcoholism, or surgical resection group. Early HCC recurrence plays a significant mediating role on the relationship between early job loss and all-cause mortality (mediated proportion 19%, 95% CI 5-31%).

Early job loss may increase risk of all-cause mortality among HCC survivors undergoing curative treatment.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related death worldwide. Contemporary advances in systemic and locoregional therapies have led to changes in peer-reviewed guidelines regarding systemic therapy as well as the possibility of downstaging disease that may enable some patients with advanced disease to ultimately undergo partial hepatectomy or transplantation with curative intent. This review focuses on all modalities of therapy for HCC, guided by modern-day practice-changing randomized data where available. The surgical management of HCC, including resection and transplantation, both of which have evolving criteria for what is considered biologically resectable and transplantable, as well as locoregional therapy (i.e., therapeutic embolization, ablation, radiation, and hepatic arterial infusion), are discussed. Historical and modern-day practice-changing trials evaluating immunotherapy with targeted therapies for advanced disease, as well as adjuvant systemic therapy, are also summarized. In addition, this article examines the critical dimension of toxicities and patient-oriented considerations to ensure a comprehensive and balanced discourse on treatment implications.

Primary liver cancer (PLC) is a prevalent tumor globally, ranking third in cancer-related mortality. The role of N4-acetylcysteine (ac4C) and N-acetyltransferase 10 (NAT10) in hepatocellular carcinoma (HCC) progression, migration, and invasion requires further elucidation. High NAT10 expression correlated with poor prognosis in HCC patients. Knockdown of NAT10 hindered HCC cell proliferation. AcRIP-seq screening revealed DDIAS as a significant downstream target of NAT10. Decreased NAT10 levels reduced DDIAS mRNA stability, leading to decreased proliferation, migration, and invasion of HCC cells upon DDIAS knockdown. Ectopic expression of DDIAS counteracted the effects of NAT10 knockdown by modulating the PI3K/AKT pathway. NAT10 was found to be elevated in HCC tissues compared to normal tissues, promoting HCC progression and correlating with shorter overall survival in patients. Mechanistically, NAT10 regulated HCC progression through the ac4C-DDIAS-PI3K-AKT axis.

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib's antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.

Hepatocellular carcinoma is the seventh most common kind of cancer worldwide and the second largest cause of cancer-related deaths in males, behind lung cancer. Globally, 866,000 people were diagnosed with hepatocellular carcinoma (HCC) in 2022, and nearly 42,240 new cases will be identified in 2025 in the United States. Using stem cells obtained from bone marrow can effectively reduce the number of malignant tumor cells through the induction of an epigenetic impact. We obtained bone marrow-derived mesenchymal stem cells (BM-MSCs) from mice and collected the conditioned medium (CM) from cultured cells with 90% confluency. The effect of the CM was identified using both 2D and 3D sphere cultures of wild-type human liver cancer cell line (HepG2), considering variations in sphere size and percentage. A cell death study was conducted using the cell cytotoxicity (MTT) kit, while the quantity of stem cells was determined by immunohistochemistry and gene expression analysis. The effectiveness of our therapy was demonstrated by an in vivo assessment of BM-MSCs through intravenous injection and the currently available anticancer drug cisplatin. In vitro, the combination treatment resulted in a synergetic effect, leading to 74% cell death in both adherent and spherical cultures when treated with 25 µM of cisplatin and 90%CM. In vivo, the histological study indicated a decrease in tumor size and number following treatment with cisplatin and BM-MSCs. The study lasted 18 weeks and revealed that the body weight of mice improved across all treatment groups, with the combination group exhibiting the most significant improvement. Both in vitro and in vivo studies showed the synergetic effect of cisplatin and isolated conditioned medium. Our study aimed to identify more efficient therapeutic approaches utilizing stem cells and existing marketed medications to minimize adverse effects with better efficacy.

Hepatocellular carcinoma (HCC) is an increasing global health burden, driven by demographic shifts and the growing prevalence of risk factors such as non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the majority of NAFLD patients being in the non-cirrhotic stage, there is a notable lack of data on HCC incidence and risk factors, making it challenging to implement effective public health screening and prevention strategies.

This study conducted a longitudinal analysis of a nationwide cohort of NAFLD patients using big data from the National Health Insurance Service of South Korea to assess HCC incidence and risk factors, focusing on non-cirrhotic patients. NAFLD was identified through ICD-10 codes and refined using a fatty liver index (FLI) score above 30.

A total of 529,811 patients were enrolled. After a washout period, 36,760 patients were newly diagnosed with NAFLD. The incidence rate of HCC per 100,000 person-years was 10.00 in healthy controls and 31.66 in NAFLD patients, further divided into 24.87 in non-cirrhotic NAFLD and 721.5 in cirrhotic NAFLD. In the 1:1 Propensity Score Matched analysis, HCC incidence in non-cirrhotic NAFLD was 24.89 per 100,000 person-years compared to 9.72 in matched healthy controls, yielding an adjusted hazard ratio (HR) of 2.69 (95 % CI 1.33-5.44). Multivariate Cox regression analysis indicated that both cirrhotic and non-cirrhotic NAFLD significantly increased the risk of developing HCC, with additional factors such as age, male sex, and type 2 diabetes. A subsequent analysis of non-cirrhotic NAFLD patients confirmed that advanced age and male sex remained significant risk factors for the development of HCC.

This study demonstrates that non-cirrhotic NAFLD patients, particularly males and those aged 70-79 years, have a significantly increased risk of HCC compared to healthy controls. Given the applicability of NAFLD concepts to MASLD, our findings could provide insights for identifying high-risk individuals within the MASLD spectrum and developing effective strategies to reduce the risk of HCC.

Hepatocellular carcinoma (HCC), a highly aggressive liver malignancy, is often associated with disrupted calcium homeostasis. Store-operated calcium entry (SOCE), involving components such as STIM1, Orai1, and SARAF, plays a critical role in calcium signaling and cancer progression. While STIM1 and Orai1 have been extensively studied, SARAF's role as a negative regulator of SOCE in HCC remains poorly understood. This preliminary study investigated SARAF's effects on calcium homeostasis, proliferation, and migration in HepG2 liver cancer cells, providing initial evidence of its tumor-suppressive role. SARAF expression was modulated using siRNA knockdown and overexpression plasmids, with validation by qRT-PCR. Functional assays demonstrated that SARAF silencing increased proliferation by 50% and migration by 40% (p < 0.05), while SARAF overexpression reduced proliferation by 50% and migration by 45% (p < 0.01), highlighting its tumor-suppressive role. Intracellular calcium levels, elevated in HepG2 cells, were partially restored by SARAF overexpression, though SARAF silencing did not further disrupt calcium regulation. These findings suggest that SARAF negatively regulates proliferation and migration in HCC, potentially through its role in maintaining calcium homeostasis. SARAF represents a promising therapeutic target in HCC. Future studies should explore the downstream molecular mechanisms governing SARAF's effects, investigate its role in other cancers, and assess its clinical potential for liver cancer therapy.

Studies have shown a change in the etiological profile of liver cancer globally. We aimed to analyze the burden and changes in etiology of liver cancer in the Asia-Oceania region.

The burden of liver cancer in Asia-Oceania was estimated using data from the 2021 Global Burden of Disease (GBD) Study. The analysis included age-standardized incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life years (DALY) per 100 000 population.

The Asia-Oceania region contributed 68.6%, 68.8%, and 67.3% of the global incidence, prevalence, and mortality of liver cancer in 2021. In 2021, Mongolia, Tonga, and South Korea had the highest ASIR, ASPR, and ASMR, whereas Australia, New Zealand, and Guam had the greatest increase in incidence and mortality rates. Viral hepatitis remained the most common etiology of liver cancer, with 47.7% and 26.1% of cases being related to hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. Around 14.5% and 7.1% of cases were related to alcohol and nonalcoholic steatohepatitis (NASH), respectively; however, the annual change in the ASIR was the highest for NASH. Alcohol, drug abuse, tobacco use, and metabolic syndrome, contributed to 15.2%, 11.7%, 11.5%, and 9.0% of liver cancer mortality in 2021; however, the change in death from 1990 to 2021 was the highest for metabolic syndrome.

Viral hepatitis remains the most common cause of liver cancer, with NASH having the highest annual rate of change in ASIR and liver cancer deaths in Asia-Oceania.

Hepatocellular carcinoma (HCC) was associated with high morbidity and mortality, representing a significant health challenge. Chondroitin sulfate (CS), a glycosaminoglycan composed of glucuronic acid and N-acetylgalactosamine, is implicated in HCC progression through its role in cancer cell migration and proliferation as well as interactions with cell surface receptors integrin β-1 and CD44. Chondroitin polymerization factor 2 (CHPF2), the key to CS synthesis, has an undefined role in HCC. Our study aims to demonstrate that decreasing CHPF2 enzyme activity can inhibit the migration and proliferation of HCC cells. Bioinformatics analysis and in vitro experiments on clinical HCC samples confirmed the knockdown of CHPF2 inhibited HCC cell proliferation and migration. We further explored Rabdosia rubescens, a plant used in cancer therapy, for its potential to modulate CHPF2. Structural biology and ligand fishing identified ponicidin, a compound that significantly suppresses HCC cell growth and migration in both in vitro and in vivo models. These findings propose CHPF2 as a novel biomarker and ponicidin as a potential therapeutic agent for HCC management.

For patients with liver cancer, a widespread and lethal tumor on a global scale, chemotherapy and immunotherapy are often the top choices. Paclitaxel, a widely administered chemotherapy drug, faces the dual issues of poor tumor response rates and the rapid onset of chemoresistance. This study delves into the functions of SIRT6 and miR-338-3p in malignancy and paclitaxel resistance of liver cancer cells. Bioinformatics and qRT-PCR were engaged to predict and examine expression profiles of SIRT6 and miR-338-3p in liver cancer tissues and cell lines. A paclitaxel-resistant cell line (MHCC97-PTX) was established for dissecting cellular responses to drug treatment. CCK-8 and colony formation tests measured cell vitality and proliferation, respectively. Flow cytometry assessed apoptotic cell death, and the paclitaxel IC50 values were derived for each group. We utilized online tools to predict miR-338-3p as an upstream regulator of SIRT6, and a dual-luciferase reporter assay verified their direct interaction. SIRT6 is abundantly expressed in liver cancer tissues and cells. SIRT6 knockdown decreased cell vitality and proliferation while promoting apoptosis and paclitaxel sensitivity. miR-338-3p, an upstream regulator of SIRT6 in liver cancer cells, binds to SIRT6 and downregulates its expression, modulating cell malignancy and drug resistance. The duo of miR-338-3p and SIRT6 can drive the aggressiveness and chemoresistance of liver cancer, emerging as hopeful candidates for biomarkers and therapeutic targets.

Controversy remains regarding liver resection (LR) and radiofrequency ablation (RFA) for patients with single hepatocellular carcinomas (HCCs) measuring 3 cm or less. The purpose of our study was to compare the prognosis between LR and RFA in patients with solitary HCCs ≤3 cm.

The meta-analysis followed the PRISMA guidelines and the Cochrane Handbook. All RCTs and cohort studies that compared LR versus RFA in patients with solitary HCCs ≤3 cm were comprehensively searched in the PubMed, Cochrane Library, Embase, and Web of Science databases up to 30 January 2024. The primary endpoints were overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS).

A total of 6356 patients with solitary HCCs ≤3 cm and 5829 patients with solitary HCCs ≤2 cm from 39 included studies were analyzed (LR = 5759, RFA = 6426). The present meta-analysis of two RCTs showed no statistically significant difference in OS between LR and RFA. However, the meta-analysis of cohort studies revealed that, compared with RFA, LR conferred a superior OS advantage (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.68-0.93, P = 0.005). There was a significant improvement in the DFS rate with LR over RFA (HR = 0.63, 95% CI: 0.49-0.81) and in the RFS rate (HR = 0.65, 95% CI: 0.55-0.76). Compared with RFA, LR resulted in better OS (HR = 0.73, 95% CI: 0.54-0.97), DFS (HR = 0.74, 95% CI: 0.67-0.82), and RFS (HR = 0.71, 95% CI: 0.57-0.90) in patients with a solitary HCC lesion ≤2 cm.

Evidence from cohort studies suggested that in patients with a solitary HCC lesion ≤3 cm, LR is preferable to RFA. Additional RCTs are needed to confirm the validity of this evidence.

To validate the efficacy and safety of thymosin α-1 combined with lenvatinib plus sintilimab in the treatment of unresectable hepatocellular carcinoma. Patients with unresectable hepatocellular carcinoma treated with lenvatinib plus sintilimab at the People's Hospital of Guangxi Zhuang Autonomous Region from January 2020 to June 2022 were retrospectively analyzed. The patients were divided into an experimental group and a control group based on their therapeutic regimens: thymosin α-1 plus lenvatinib and sintilimab (experimental group), and lenvatinib plus sintilimab (control group). The primary endpoints were overall survival and progression-free survival. Tumor response was evaluated according to mRECIST criteria, and the partial response, complete response, stable disease, progressive disease, object response rate, and disease control rate of the two groups were compared. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The median overall survival of all patients was 13.0 months (95% CI 10.587-15.413). The experimental group had a longer median overall survival than the control group (16 months vs. 11 months, P = 0.018). The median progression free survival of all patients was 5.0 months (95% CI 3.721-6.279). The experimental group had a longer median progression-free survival than the control group (7 months vs. 4 months, P = 0.006). The objective response rate of the experimental group was 55.8% (24/43), and of the control group's 34.7% (17/49) (P = 0.042). The disease control rate of the experimental group was 76.7% (33/43), while the control group had a rate of 59.2% (29/49) (P = 0.073). There was no significant difference in the incidence of grade 1-2 adverse events or grade 3-4 adverse events between the two groups (P > 0.05). Thymosin α-1 combined with lenvatinib plus sintilimab is an effective and safe therapeutic regimen in unresectable hepatocellular carcinoma.

Hepatic resection (HR) and liver transplantation (LT) are potentially curative treatments for Hepatocellular carcinoma (HCC). The aim of this study was to analyze the survival of patients with HCC and indications for surgical treatment (HR or LT) in a high-volume center.

This was a retrospective cohort study of consecutive patients with HCC and indications for LT or HR from May 2006 to July 2019. Analysis of overall survival (OS) and disease-free survival (DFS) rates, univariate analysis and construction of a multivariable model to identify risk factors were performed.

A total of 744 patients with HCC were evaluated, 563 (75.6%) of whom were enrolled in waiting list for LT and 181 (24.4%) of whom underwent HR. Among the patients enrolled in the waiting list, 362 (64.3%) underwent LT, whereas 201 (35.7%) remained on the waiting list (WL). From the group of 201 patients on the waiting list, 97 (48.2%) were removed from the list due to tumor progression beyond the Milan criteria (MC), and 83 (41.3%) died while waiting for the transplant. In the WL group, 97 (48.2%) patients were removed from the list due to tumor progression beyond the MC, another 83 (41.3%) patients died while waiting for the LT. The OS rates of the LT group were 77.4%, 67.5% and 56.8%, whereas those of the WL + LT (intention-to-treat) group were 59.9%, 47.3%, and 39.9%, and the HRs were 82.8%, 49.3%, and 33.4% at 1, 5 and 10 years, respectively (p = 0.001). Donor age (p = 0.002) and cold ischemia time (p < 0.001) were independent factors related to OS in the LT group, whereas the presence of significant portal hypertension (p < 0.001), alpha-fetoprotein (AFP) value (p < 0.001) and MC (p = 0.002) were independent factors for HR. The DFS rates for HR were 74.9%, 40.0% and 31.0%, and those for LT were 97.9%, 92.0% and 90.9% at 1, 5 and 10 years, respectively (p < 0.001). Higher AFP levels were identified as an independent factor for lower DFS in both groups.

The present study revealed that the OS of patients listed for LT was greater in the first year than in the second year and that the results were similar to those of the HR in an intention-to-treat analysis. However, patients who achieve LT have better long-term outcomes, especially disease-free survival.

Disulfidptosis is a newly discovered programmed cell death pathway that may be connected to tumorigenesis and development, showing promise as a novel treatment strategy for cancer. This study aims to construct a prognostic model of disulfidptosis-related Long non-coding RNAs (DRLRs) within the Asian HCC population and to investigate the impact of DRLRs on HCC.

Utilising a combination of univariate Cox, Lasso-Cox, and multivariate Cox analyses, five pivotal DRLRs (AC099850.3, ZNF337-AS1, LINC01138, AL031985.3, AC131009.1) were identified, forming a robust prognostic signature. Subsequent validations included Receiver Operating Characteristic (ROC) and Concordance Index analyses, alongside Principal Component Analysis. Comprehensive bioinformatics analysis was performed on the hub DRLRs, followed by experimental validation using quantitative real-time polymerase chain reaction and cellular functional assays.

The risk score independently predicted prognosis, outperforming traditional clinical-pathological factors across varying ages, tumour stages, and pathological classifications in the cohort. A nomogram integrating these variables demonstrated capability in forecasting survival. Multivariate analysis confirmed that the risk score and AJCC TNM staging are independent prognostic factors for predicting overall survival (OS) in Asian HCC patients (both P < 0.001). The prognostic model's ROC area under the ROC values for 1-, 3-, and 5-year predictions were 0.837, 0.794, and 0.783, respectively, indicating its strong diagnostic and prognostic value. Pathway and immune landscape analyses elucidated the biological underpinnings and immune modulations associated with the high-risk group. Immune landscape analysis indicated that both immunescore (P < 0.001) and estimatescore (P < 0.05) were significantly decreased in the high-risk group, with both specific and non-specific immune responses being significantly suppressed, while the tumour immune dysfunction and exclusion score was notably increased (P < 0.001). Tumour mutational burden (TMB) analysis revealed a significantly higher TMB in the high-risk group (P = 0.033) and shorter OS for HCC patients in the high TMB subgroup (P = 0.002). Notably, Potential chemotherapeutic agents (PFI3, 5-Fluorouracil, BPD-00008900, GDC0810, and AZ6102) were identified for high-risk group. Experimental validations through quantitative PCR and in vitro assays confirmed the deregulation of these DRLRs in HCC, with functional studies highlighting the potential of ZNF337-AS1 silencing in curtailing tumour invasiveness.

Our investigations validate a DRLR-based risk scoring model as an effective prognostic tool for Asian HCC. This model not only enhances understanding of disulfidptosis's role in HCC but also facilitates personalised treatment strategies, potentially improving patient outcomes.

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

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

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

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

Hepatitis C virus (HCV) is the predominant viral cause of hepatocellular carcinoma (HCC). Early detection and use of reliable biological markers can improve survival for HCC patients. MiR-485-5p was identified as a tumor-suppressing microribonucleic acid (miRNA) in some human cancers and was recently found to be downregulated in HCC tissues, signifying its utility as a promising biomarker. We aimed to investigate the potential role of circulating miR-485-5p as a novel diagnostic and prognostic biomarker for HCV-related HCC. This case-control study included 50 patients with HCC associated with HCV, 50 patients with HCV-related liver cirrhosis, and 50 healthy controls. History gathering, physical examination, laboratory, and imaging assessments were performed. A quantitative real-time polymerase chain reaction was used to measure miR-485-5p levels. Serum miR-485-5p values demonstrated a stepwise decline pattern from the control group to cirrhotic patients, with the HCC group exhibiting the lowest levels (p < 0.001). HCC patients with early BCLC stages had significantly lower miR-485-5p levels than those with late stages (p = 0.004). The miR-485-5p displayed a better performance in predicting HCV-related HCC with a greater area under the ROC curve (AUC) than alpha-fetoprotein (AFP) (AUC and sensitivity 0.921 and 92.0 versus 0.704 and 64.0, respectively) (p < 0.001). Also, its performance in predicting HCC prognosis surpassed that of AFP (AUC and sensitivity 0.872 and 85.19 versus 0.695 and 62.96, respectively) (p < 0.001). Circulating miR-485-5p is a promising, accurate, and noninvasive biomarker for the early detection and prediction of prognosis in patients with HCV-linked HCC.

Liver cancer is a significant global health concern, with projections indicating that the incidence of morbidity may surpass one million cases by 2025. Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer, constituting approximately 90% of all liver cancer diagnoses. Infections caused by the hepatitis B virus (HBV) and hepatitis C virus (HCV) are recognized as primary risk factors for the development of HCC. However, non-alcoholic steatohepatitis (NASH), which is often linked to metabolic syndrome or diabetes, is increasingly being recognized as a prevalent risk factor in Western populations. Furthermore, HCC associated with NASH exhibits distinct molecular pathogenesis. Patients diagnosed with HCC have access to a range of therapeutic interventions, including liver transplantation, surgical resection, percutaneous ablation, radiation therapy, and transarterial and systemic therapies. Consequently, effective clinical decision-making requires a multidisciplinary approach to adapt individualized treatment plans based on the patient's tumor stage, liver function, and overall performance status. The approval of new first- and second-line pharmacological agents, along with the establishment of immune checkpoint inhibitor therapies as standard treatment modalities, has contributed to an improved prognosis for patients with HCC. Nevertheless, the optimal sequencing of these therapeutic agents remains to be elucidated, highlighting the urgent need for predictive biomarkers to inform treatment selections. Traditional Chinese Medicine (TCM) has demonstrated potential as a complementary and alternative therapeutic approach for liver cancer, warranting further investigation. This review aimed to examine the comprehensive treatment of HCC through the lens of TCM, informed by the current understanding of its epidemiology, diagnosis, and pathophysiology.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The complex interplay between estrogen deficiency, visceral fat accumulation, metabolic syndrome (MetS), and inflammation accelerates disease progression, increases cardiovascular (CV) risk, and triggers a cycle of worsening adiposity, metabolic dysfunction, and psychological problems, including eating disorders. Weight loss in postmenopausal women can significantly improve both metabolic and psychological outcomes, helping to prevent MASLD and related conditions. This review examines the prevalence of MASLD, its comorbidities (type 2 diabetes T2D, CV, mental disorders), pathogenetic mechanisms, and pharmacological treatment with GLP-1 receptor agonists (GLP1-RAs), with a focus on postmenopausal women. Given the use of GLP1-RAs in the treatment of obesity and T2D in MASLD patients, and the increase in MetS and MASLD after menopause, this review analyzes the potential of a stable GLP-1-estrogen conjugate as a therapeutic approach in this subgroup. By combining the synergistic effects of both hormones, this dual agonist has been shown to increase food intake and food reward suppression, resulting in greater weight loss and improved insulin sensitivity, glucose, and lipid metabolism. Therefore, we hypothesize that this pharmacotherapy may provide more targeted therapeutic benefits than either hormone alone by protecting the liver, β-cells, and overall metabolic health. As these effects are only supported by preclinical data, this review highlights the critical need for future research to evaluate and confirm the mechanisms and efficacy in clinical settings, particularly in postmenopausal women.

This study aimed to develop a radiomics model characterized by 68Ga-fibroblast activation protein inhibitors (FAPI) positron emission tomography (PET) imaging to predict microvascular invasion (MVI) of hepatocellular carcinoma (HCC). This study also investigated the impact of varying thresholds for maximum standardized uptake value (SUVmax) in semi-automatic delineation methods on the predictions of the model.

This retrospective study included 84 HCC patients who underwent 68Ga-FAPI PET and their MVI results were confirmed by histopathological examination. Volumes of interest (VOIs) for lesions were semi-automatically delineated with four thresholds of 30%, 40%, 50%, and 60% for SUVmax. Extracted shape features, first-, second- and higher-order features. Eight PET radiomics models for predicting MVI were constructed and tested.

In the testing set, the logistic regression (LR) model achieved the highest AUC values for three groups of 30%, 50%, and 60%, with values of 0.785, 0.896, and 0.859, respectively, while the random forest (RF) model in 40% group obtained the highest AUC value of 0.815. The LR model in 50% group and the extreme gradient boosting (XGBoost) model in 60% group achieved the highest accuracy, each at 87.5%. The highest sensitivity was observed in the support vector machine (SVM) model in 30% group, at 100%.

The 68Ga-FAPI PET radiomics model has high efficacy in predicting MVI in HCC, which is important for the development of HCC treatment plan and post-treatment evaluation. Different thresholds of SUVmax in semi-automatic delineation methods exert a degree of influence on performance of the radiomics model.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Radiofrequency ablation (RFA) can be utilized in elderly patients and those with cirrhosis with reduced functional liver reserve as it is less invasive. The arfa RFA system is the first system to offer a linear mode. However, the differences in performance between the linear and existing (nonlinear) modes remain unknown.

This retrospective observational study compared the performance of the linear (linear group) and nonlinear RFA modes (nonlinear group) in HCC.

Data of 425 patients with one to three HCC tumors measuring ≤ 3 cm who underwent RFA were analyzed. Recurrence (local and distant), survival, and complication rates between the linear and nonlinear groups were determined.

The intrahepatic distant recurrence rate was lower in the linear group than in the nonlinear group (p < 0.05). Multivariate analysis showed that the high platelet count, low AFP-L3 levels, initial case, and linear mode were independent factors associated with a low intrahepatic distant recurrence rate following RFA. Liver disease-related survival, HCC survival, overall survival of the initial HCC, local recurrence, and complication rates were comparable between the linear and nonlinear groups.

The linear mode of the RFA protocol results in a lower intrahepatic distant recurrence rate compared with the nonlinear protocol.

Primary liver cancer is a major global health challenge, of which hepatocellular carcinoma is the most common. For patients with advanced liver cancer, Sorafenib is a first-line targeted drug that occupies a dominant position in clinical applications. Sorafenib is a multi-kinase inhibitor commonly used in clinical practice, which can effectively inhibit tumor cell proliferation, promote cell apoptosis, and inhibit angiogenesis. However, the emergence of drug resistance has hindered the development of treatment programs, which is an urgent problem to be solved. Recent studies have revealed many mechanisms and influencing factors of Sorafenib resistance (such as epigenetic regulation, programmed cell death, metabolic reprogramming, and tumor microenvironment changes). This review not only summarizes the above mechanisms, but also summarizes the combined application of Sorafenib with other drugs (such as molecular targeted drugs, other anti-angiogenesis drugs, cytotoxic drugs, immunotherapy drugs, etc .). Finally, potential strategies and research directions to overcome drug resistance (such as targeting epigenetic pathways or metabolic reprogramming) are discussed to provide suggestions for future in-depth research and clinical applications.

This study comprehensively assessed the burden of liver cancer due to hepatitis B (LCHB) from 1990 to 2021, analyzing temporal trends in disease burden and associations with age, period and birth cohort.

Age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR) of LCHB from 1990 to 2021 were collected from the Global Burden of Disease (GBD) 2021. Joinpoint regression analysis estimated long-term trends. Age-period-cohort analysis evaluated the independent effects of age, period and cohort. Decomposition analysis elucidated the impact of population growth, aging and epidemiological changes on the burden.

Between 1990 and 2019, the ASIR and ASMR of LCHB witnessed an overall declining trend worldwide, with a notably higher burden in males compared to females. The highest ASIR and ASMR were observed in the middle socio-demographic index (SDI) region, while the lowest were in the low-middle SDI region, with substantial differences across countries. Age-period-cohort analysis revealed an initial increase in risk followed by a decline with advancing age, with the burden primarily affecting the elderly. Decomposition analysis indicated that population growth and aging were the primary drivers of the increase in incident cases and deaths.

From 1990 to 2021, the ASIR and ASMR of LCHB decreased globally. However, population growth and aging contributed to an increase in the absolute numbers of incident cases and deaths. The risk burden increased with age, and favourable period and cohort effects were found in all SDI regions.

Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer and is frequently linked to underlying chronic liver conditions such as hepatitis B, hepatitis C, and cirrhosis. Despite the progress achieved in the field of oncology, HCC remains a significant clinical challenge, primarily due to its typically late-stage diagnosis and the complex and multifaceted nature of its tumor biology. These factors contribute to the limited effectiveness of current treatment modalities and result in poor patient prognosis. Emerging research has underscored the vital role of microRNAs (miRNAs)-small, non-coding RNA molecules that play a pivotal part in the post-transcriptional regulation of gene expression. These miRNAs are integral to a wide array of cellular functions, including proliferation, apoptosis, and differentiation, and their dysregulation is closely associated with the pathogenesis of various cancers, notably HCC. A major focus in recent studies has been on the epigenetic regulation of miRNAs through methylation, a key mechanism that modulates gene expression. This process, involving the addition of methyl groups to CpG islands in the promoter regions of miRNA genes, can result in either gene silencing or activation, influencing the expression of oncogenes and tumor suppressor genes. Such alterations have profound implications for tumor growth, metastasis, and resistance to treatment. Evidence suggests that aberrant miRNA methylation can serve as a powerful biomarker for early detection and prognosis in HCC and may present novel opportunities for therapeutic intervention. This review aims to provide a comprehensive overview of the current landscape of miRNA methylation in HCC, elucidating its significance in the molecular mechanisms of liver cancer and examining its potential for clinical application. By exploring the diagnostic and therapeutic potential of miRNA methylation, we seek to highlight its value in enhancing personalized treatment strategies and improving patient outcomes.

This study investigated the long-term prognosis and clinical course of patients who survived for more than 5 years after hepatocellular carcinoma (HCC) diagnosis.

This retrospective cohort study used data from the Korean National Health Insurance Service database. A total of 35,348 subjects newly diagnosed with HCC between January 2008 and December 2010 were followed up until December 2018.

A total of 11,514 (32.6%) survived for 5 years after diagnosis of HCC among 35,348 patients diagnosed with HCC. Long-term survivors (≥ 5 years) had a higher proportion of females, younger age, more frequent aetiology of hepatitis B virus, less frequent liver cirrhosis, diabetes mellitus and hypertension, and received curative treatment more frequently than nonsurvivors (< 5 years). The additional 1-, 3- and 5-year cumulative survival probabilities were 90.7%, 77.6% and 68.4% respectively. Patients who underwent curative treatment as the first treatment for HCC showed a higher additional 5-year cumulative survival probabilities than those treated with noncurative therapy (74.5% vs. 64.2%). Among the long-term survivors, 44.4% underwent HCC retreatment 5 years after HCC diagnosis. The additional 5-year cumulative survival probability was 54.9% in the HCC retreatment group. The overall 5- and 10-year cumulative probabilities of second primary malignancies in long-term survivors were 15.36% and 27.54% respectively. The most frequent second primary malignancy was prostate cancer, followed by colorectal and pancreatic cancers.

Our study highlights that a significant proportion of patients with HCC achieve long-term survival beyond 5 years, with favourable outcomes associated with curative treatments.

The controlling nutritional status score (CONUT) has been utilized for prognostication of several cancers but its utility for hepatocellular carcinoma (HCC) is still unclear. We reviewed evidence on the ability of CONUT to predict overall survival (OS) and disease-free survival (DFS) in patients with HCC.

Online repositories of PubMed, Embase, CENTRAL, and Web of Science were searched by two reviewers for English language studies and were available before 15th March 2024. Hazard ratio (HR) and 95% confidence intervals were calculated for both OS and DFS.

A total of fourteen studies were available. Meta-analysis showed that CONUT was a significant predictor for OS (HR: 1.64 95% CI: 1.30, 2.06) and DFS (HR: 1.32 95% CI: 1.17, 1.50) in HCC. The effect size failed to change in significance on sensitivity analysis. Subgroup analysis based on country and treatment of HCC did not change the results. Subgroup analysis and meta-regression showed that a higher CONUT cut-off led to a stronger association between CONUT and OS in HCC.

CONUT can be an easy-to-use and rapid prognostic indicator for HCC. High CONUT scores are associated with worse OS and DFS.

Sorafenib resistance is a significant hurdle in the treatment landscape of hepatocellular carcinoma (HCC). Lipocalin 2 (LCN2), a secretory glycoprotein that transports lipophilic molecules across cell membranes, is thought to affect the s therapeutic efficacy of sorafenib. Despite its importance, the detailed regulatory pathways involving LCN2 are still being deciphered. We probed the correlation between LCN2 expression and sorafenib resistance in HCC cells. Through the modulation of LCN2 levels, we investigated its role in cell proliferation, apoptosis, and its regulatory effects on autophagy-driven ferroptosis. With the aid of hTFtarget and JASPAR databases, ESR1 was pinpointed as a transcriptional inhibitor of LCN2. The impact of the ESR1-LCN2 axis on sorafenib resistance in HCC was then examined in vitro and validated in a xenograft tumor mouse model. In HCC cells, elevated LCN2 levels were found to be associated with resistance to sorafenib. Depletion of LCN2 resulted in attenuated HCC cell growth and elevated rates of apoptosis and ferroptosis. Overexpression of LCN2 had the opposite effect, promoting cell proliferation and suppressing cell death pathways, a response that could be overridden by autophagy agonists. ESR1 suppressed LCN2 transcription, which in turn activated autophagy-mediated ferroptosis, mitigating sorafenib tolerance in HCC and enhancing the therapeutic index. ESR1 targets LCN2 transcription to initiate autophagy-driven ferroptosis, thereby reducing sorafenib resistance in HCC cells.

The distribution of major causes of liver cancer (LC) in the United States (US) has changed significantly over time. This study analyzes recent temporal trends in the causes of LC in the US from 1990 to 2021 and predicts future trends.

We obtained detailed data on LC in the US from the Global Burden of Disease (GBD) 2021 study. Estimated annual percentage change (EAPC) values for LC in the US were then calculated using linear regression models. An exponential smoothing (ES) projection model and Bayesian Age-Period-Cohort (BAPC) projection model were then used to predict the future disease burden of LC. Risk factors for LC were also assessed.

In 2021, the disease burden of LC in the US was significantly higher than in 1990. Hepatitis C virus (HCV)-associated LC resulted in the greatest burden of disease. The fastest growing burden of disease was attributed to metabolic dysfunction-associated steatotic liver disease (MASLD)-associated LC. Higher burdens of disease were seen in older and male populations.

In the US, the disease burden of LC from different etiologies continues to rise. As such, targeted prevention and control strategies should be developed to address these unique disease characteristics.

Mutations in the TP53 gene had been attributed to the development of liver cancer. Hepatocellular carcinoma (HCC) and liver tumour are liver diseases having high mortality rates in several populations. There is no information on the TP53 gene polymorphism among liver diseases patients in Calabar, Nigeria. This study investigated the genetic polymorphism of TP53 among HCC and liver tumour in Calabar. This research was carried out in the University of Calabar Teaching Hospital, Calabar. Blood samples were collected from 35 clinically diagnosed hepatocellular carcinoma and 10 tumour patients and 10 healthy controls. DNA was extracted from all blood samples and Polymerase Chain Reaction (PCR) was performed using specific primers. The PCR amplicons were digested using Hae III restriction enzyme and the genotypic and allelic frequencies was determined. Demographic data among participants showed that males were 68.9% (31), females (31.1%; 14), sex ratio (2.2: 0.5), mean age was 41.51 ± 2.13 years with an odds ratio of 1.25. The distribution of participants according to marital status were 33(73.3%), 10(22.2%), and 2(4.4%) for married, single, and widowed respectively. The participants were from different extractions with varied representations of Yakurr (22.2%, 10), Efik (20%, 9), Boki (13.3%, 6), Ogoja (13.3%, 6), Annang (8.8%, 4), Ibibio (2.2%, 1) and Igbo (2.2%, 1) and respectively. Approximately, 64.7% (30) of the chronic liver diseases were from the Central and Northern part of Cross River State. The risk factors were HCV infection, HBsAg+, alcoholism, smoking, consumption of groundnuts that may have been contaminated with aflatoxin and family history of the disease. PCR product yielded 254 bp and digested PCR product showed homozygous TT mutation (27), heterozygous GT mutation (17) and homozygous GG wild type (1) in cases. The overall TP53 gene mutation frequency was 46.32% (44). The frequency of G allele, T allele, GG, GT and TT were 0.21, 0.79, 0.04, 0.33 and 0.62 respectively among cases, while GG (wild type) was only detected among controls in the study population. The genotypic and allelic frequencies conform to Hardy-Weinberg equilibrium meaning that the forces of evolution were not acting on the locus. There were significant differences in the genotypic proportions of the TP53 gene polymorphism among patients and controls. This study on the TP53 gene polymorphism will serve as baseline information on the molecular etiology of hepatocellular carcinoma and liver tumour in Cross River State.

Hepatocellular carcinoma (HCC) is expected to become the third most common cause of cancer death worldwide by 2030. The increase in HCC is in large part due to the rising prevalence of risk factors such as type 2 diabetes mellitus (T2DM). Up to 1 in 20 people living with T2DM have liver cirrhosis, and they have a 1% to 2% incidence of HCC per year. Patients with cirrhosis enter surveillance for HCC to identify early-stage, curable tumours. A diagnosis of T2DM does not mandate testing to identify patients with cirrhosis, with testing restricted to those with additional risks. There has never been a trial and nested cost-effectiveness evaluation comparing screening all patients with T2DM for cirrhosis against usual care.

The study will use a multi-centre, unblinded individual randomised controlled trial design. The aim will be to determine the effectiveness and cost-effectiveness of screening all adults with T2DM to identify those at high risk of HCC. The recruitment strategy has been supported by patient and public involvement (PPI). Participants will be identified via an automated search of primary care records and invited to participate via text. 320 participants will be randomised for screening. The screening will include measurement of bio-markers for liver fibrosis (ELF and Fib-4) and vibration-controlled transient elastography. Another 320 participants will be randomised to standard care. Demographic and medical history data will be collected at baseline from all participants. Outcome data will be collected remotely from healthcare records. The primary outcome is the proportion of participants in each arm who are referred to HCC surveillance following testing for liver disease within 12 months of randomisation. The results will be used to calculate the incremental cost-effectiveness ratio of screening via a Markov model.

The results of this study will be presented directly to National Health Service England. Additional dissemination via conference proceedings and publication will be supported by our PPI team. Ethical approval was granted by the West of Scotland Research Ethics Service on 2 August 2023, REC reference 23/WS/0102.

ISRCTN17017677.

Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-of-field recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical rationale for combining 90Y-RE with ICIs, highlights early clinical trial data on its safety and effectiveness, and proposes key issues to be addressed in this emerging field. With optimal strategies, combination therapies can potentially result in increasing likelihood of durable and curative outcomes in later stage patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction-associated steatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex-specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex-specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed.

Numerical fluid-particle dynamics simulations, such as Computational Fluid Dynamics (CFD), are widely used to study blood flow and microsphere transport in medical treatments like radioembolization (RE), a therapy for unresectable liver tumors. RE involves injecting 90Y-labeled microspheres via a microcatheter into a hepatic artery to irradiate cancer cells. This study uses simulations on three patient-specific hepatic arteries to evaluate microsphere distribution in RE, focusing on two catheter designs: a standard end-hole catheter (EHC) and a novel multi side-hole catheter (SHC). Key parameters include cancer scenario and catheter tip position. Three performance indexes are introduced: the matching deviation index (MDI), targeting deviation index (TDI), and tumor-flow deviation index (TFDI). Results show the SHC outperforms the EHC with better MDI (3.67 vs. 8.36 percent points) and TDI (6.04 vs. 10.24 percent points) values, suggesting the SHC's cross-flow effect improves microsphere dispersion and alignment with flow split. The TDI values for SHC often match the TFDI, making the latter a potential performance predictor. The SHC demonstrates superior performance when tumors are located downstream from the catheter tip, while for localized tumors, superselective treatment is recommended, minimizing the catheter's impact on therapy.

Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and a significant global health challenge due to its high mortality rate. The epidemiology of HCC is closely linked to the prevalence of chronic liver diseases, the predominant etiology being hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, alcohol consumption, and metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD). HCC incidence varies widely globally, with the highest rates observed in East Asia and sub-Saharan Africa. This geographic disparity is largely attributed to the endemicity of HBV and HCV in these regions. In Western countries, the incidence of HCC has been rising, driven by increasing rates of alcohol abuse and the presence of steatosis liver disease. MASLD-associated HCC has a higher body mass index, a higher rate of type 2 diabetes mellitus, hyperlipidemia, hypertension, and association with cardiovascular diseases. Steatosis-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related liver disease and viral hepatitis. Prevention strategies vary by region, focusing on vaccination against HBV, antiviral treatments for HBV and HCV, alcohol moderation, and lifestyle interventions along with weight reduction to reduce obesity and incidence of MASLD-related HCC incidence.

In this study, we examined novel autoantibodies targeting tumor-associated antigens (TAAs) as biomarkers for clinical assessment of hepatocellular carcinoma (HCC) in a Chinese population.

A total of 119 patients with HCC and 130 healthy control (HC) volunteers who were age and gender matched were enrolled. The levels of circulating IgG antibodies were detected using an enzyme-linked immunosorbent test (ELISA) developed in-house with linear peptide antigens derived from Annexin A1(ANXA1) and proto-oncogene protein (MYC). The significant level was set at P ​< ​0.025 as two tests were performed.

In comparison to the HC group, plasma level of ANXA1 autoantibodies was significantly elevated in HCC patients (t ​= ​-3.174, P ​= ​0.002) but the change of plasma MYC autoantibody levels failed to reach the significance level (P ​> ​0.025). There was a significant increase in these two plasma IgG autoantibodies in male HCC patients (ANXA1: t ​= ​-3.590, P ​< ​0.001; MYC: t ​= ​-2.706, P ​= ​0.007). Pearson correlation analysis demonstrated that both anti-ANXA1 and anti-MYC IgG levels had a positive correlation with BCLC staging (both P ​< ​0.025) but a negative correlation with plasma albumin (Alb) (both P ​< ​0.025). The area under the ROC curve (AUC) values were 0.613 for anti-ANXA1 IgG assay and 0.567 for anti-MYC IgG assay. The anti-ANAXA1 IgG assay showed a high sensitivity of 31.4 ​% against the specificity of 90.0 ​% for detection of BCLC stages C ​+ ​D.

Plasma anti-ANXA1 and anti-MYC autoantibodies are likely to serve as a potential biomarker for clinical assessment of HCC prognosis, particularly in male patients.

Understanding the status and function of tumor-infiltrating immune cells is essential for improving immunotherapeutic effects and predicting the clinical response in human patients with carcinoma. However, little is known about tumor-infiltrating immune cells, and the corresponding research results in hepatocellular carcinoma (HCC) are limited.

To investigate potential biomarker genes that are important for the development of HCC and to understand how immune cell subsets react throughout this process.

Using single-cell RNA sequencing and T-cell receptor sequencing, the heterogeneity and potential functions of immune cell subpopulations from HCC tissue and normal tissue adjacent to carcinoma, as well as their possible interactions, were analyzed.

Eight T-cell clusters from patients were analyzed and identified using bioinformatics, including six typical major T-cell clusters and two newly identified T-cell clusters, among which Fc epsilon receptor 1G+ T cells were characterized by the upregulation of Fc epsilon receptor 1G, tyrosine kinase binding protein, and T cell receptor delta constant, whereas metallothionein 1E+ T cells proliferated significantly in tumors. Differentially expressed genes, such as regulator of cell cycle, cysteine and serine rich nuclear protein 1, SMAD7 and metallothionein 1E, were identified as significantly upregulated in tumors and have potential as biomarkers. In association with T-cell receptor analysis, we inferred the clonal expansion characteristics of each T-cell cluster in HCC patients.

We identified lymphocyte subpopulations and potential biomarker genes critical for HCC development and revealed the clonal amplification of infiltrating T cells. These data provide valuable resources for understanding the response of immune cell subsets in HCC.