In most countries, males have ~2-3 times higher incidence of primary liver cancer than females. Sex hormones have been hypothesized to contribute to these differences, but the evidence remains unclear. Using data from the UK Biobank, which included ~200,000 males and ~180,000 postmenopausal females who provided blood samples at recruitment, we estimated hazard ratios (HR2) and 95% confidence intervals (CI) for a doubling in hormone concentration from multivariable adjusted Cox regression for circulating total testosterone, sex-hormone binding globulin (SHBG), and free testosterone concentrations and risk of primary liver cancer. After a median of 11.8 years of follow-up, 531 cases of primary liver cancer were observed, of which 366 occurred in males and 165 occurred in females. Total testosterone and SHBG were shown to be positively associated with liver cancer risk in both males and females (Total testosterone HR2: 3.42, 95% CI:2.42-4.84 and 1.29, 0.97-1.72, respectively; SHBG HR2: 5.44, 4.42-6.68 and 1.52, 1.09-2.12, respectively). However, free testosterone was inversely associated with primary liver cancer in males (HR2: 0.42, 0.32-0.55) and no association was observed in females. When analyses compared two main liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), there was evidence of heterogeneity; associations for total testosterone and SHBG concentrations were only positively associated with HCC in both males (HR2: 3.56, 2.65-4.79 and 7.72, 6.12-9.73, respectively) and females (HR2: 1.65, 1.20-2.27 and 6.74, 3.93-11.5, respectively) but not with ICC. Further research understanding the mechanisms of how sex-steroids may influence liver cancer risk is needed.

Early assessment of hepatocellular carcinoma (HCC) risk could improve long-term outcomes in people with chronic hepatitis B virus (HBV) infection. Some existing HCC predictive scores are not easily implementable. We developed easy-to-use HCC predictive scores based on behavioural and routine bio-clinical data in people with chronic HBV infection.

Eight-year follow-up data was analysed from people with chronic HBV infection enrolled in the French ANRS CO22 HEPATHER cohort. Patients were randomly split into two samples (training/testing). A multivariable Cox model for time to HCC was estimated on the training sample. The HCC predictive score was computed by summing the points assigned to model predictors, normalising their coefficients over a 10-year age increment, and rounding to the nearest integer. The Youden index identified the score's optimal risk threshold. Comparisons with existing predictive scores were performed on the testing sample.

In the study population (N = 4370; 63% of men; 65% of < 50 years old), 56 HCC cases occurred during 25,900 follow-up person-years. Two HCC predictive scores were defined: SADAPTT (daily soft drink consumption, age, hepatitis Delta infection, unhealthy alcohol use, platelet count, heavy tobacco smoking, and HBV treatment) and ADAPTT (the same predictors except for daily soft drink consumption), with ranges 0-13 and 0-14, respectively, and values ≥ 3 indicating a high HCC risk. Their performances were similar to existing scores.

We developed two effective behaviour-based HCC predictive scores, implementable in many settings, including primary care and decentralised areas. Further studies are needed to validate these scores in other datasets.

Epidemiological evidence on meat consumption and liver cancer risk is limited and inconclusive; moreover, no prospective study has been conducted to investigate this association in China. Hence, we performed this study to examine the association of red meat, poultry, and fish consumption with the risk of liver cancer in a Chinese population.

A total of 510,048 Chinese adults of ages 30 to 79 years were included and were followed up through December 31, 2016. Red meat, poultry, and fish consumption was evaluated using an interviewer-administered laptop-based questionnaire. HRs and 95% confidence intervals (CI) for liver cancer incidence were calculated using Cox regression.

Over a mean follow-up of 9.94 years, 1,906 liver cancer cases were observed. Each 50 g/day increase in red meat (HR 0.72; 95% CI, 0.49-1.05), poultry (HR 0.93; 95% CI, 0.83-1.03), and fish (HR 0.95; 95% CI, 0.85-1.05) consumption was not associated with the risk of liver cancer in the whole study population; however, subgroup analysis revealed an inverse association with poultry consumption in rural residents but not in urban residents (Pinteraction = 0.046). The initial associations did not change materially in a series of sensitivity analyses.

Red meat and fish consumption is not associated with the risk of liver cancer in this Chinese population. The inverse association with poultry consumption in Chinese rural residents should be interpreted with caution.

This is the first prospective study examining the association between meat consumption and the risk of liver cancer in the Chinese population.

The global epidemiology of HCC is shifting due to changes in both established and emerging risk factors. This transformation is marked by an emerging prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, alongside traditional risks such as viral hepatitis (HBV and HCV), and exposure to chemical agents like aflatoxin, alcohol, tobacco, and air pollution. This review examines how environmental exposures and evolving liver pathology, exacerbated by lifestyle and metabolic conditions, are contributing to the rising worldwide incidence of HCC. Effective prevention strategies must not only address traditional risk factors through vaccination and therapeutic measures but also confront metabolic and socioeconomic disparities through comprehensive public health efforts. As the burden of liver cancer continues to grow, particularly in resource-limited settings, an expansive and inclusive approach is vital for mitigating its impact across diverse populations.

HBV genotype C, particularly subgenotype C2, is associated with an elevated risk of HCC and aggressive disease activity. We previously identified a nonsynonymous sV184A variant in the HBsAg region, predominantly in HBV subgenotype C2. This study investigates the mechanistic role of the sV184A variant in promoting liver disease progression. Analysis of 109 chronically HBV-infected patients revealed that the sV184A variant correlates with significantly elevated HBV DNA. Both patient data and public database indicated that sV184A is associated with high frequency of BCP mutations, however, the high HBV DNA in the sV184A group are independent of the presence of BCP mutations. In vitro and in vivo studies demonstrated that the sV184A variant enhances HBV replication and induces ER stress via the PERK-eIF2α-CHOP pathway, leading to apoptosis. HBV large surface (LHB)(LHB) protein was found to be a key factor, responsible for the strong ER stress, as the sV184A variant increases LHB protein stability. Pharmacological inhibition of PERK signaling or mutation of the LHB mitigated HBV proliferation and apoptosis induced by the sV184A variant. The sV184A variant specific to HBV subgenotype C2 significantly promotes HBV replication and apoptosis, serving as a driver of advanced liver disease and potentially increasing mutation rates in affected patients.

Management of cirrhosis sequelae is critical in providing the most options for patients with hepatocellular carcinoma (HCC). Compensated liver disease is the ideal state for HCC patients who may require resection, locoregional therapies, or liver transplantation. Portal hypertension complications, suboptimal nutrition, and frailty are common barriers to various HCC treatments. For patients with advanced HCC, systemic therapies are altering the approach to multifocal, unresectable HCC, but similar barriers exist related to managing cirrhosis complications. Frequently, managing the underlying liver disease etiology is a key component to enabling HCC treatment.

Immune checkpoint inhibitors have proven efficacy against hepatitis B-virus positive hepatocellular. However, Immunotherapy-related adverse reactions are still a major challenge faced by tumor immunotherapy, so it is urgent to establish new methods to effectively predict immunotherapy-related adverse reactions.

Multi-machine learning model were constructed to screen the risk factors for irAEs in ICIs for the treatment of HBV-related hepatocellular and build a prediction model for the occurrence of clinical IRAEs.

Data from 274 hepatitis B virus positive tumor patients who received PD-1 or/and CTLA4 inhibitor treatment and had immune cell detection results were collected from Henan Cancer Hospital for retrospective analysis. Models were established using Lasso, RSF (RandomForest), and xgBoost, with ten-fold cross-validation and resampling methods used to ensure model reliability. The impact of influencing factors on irAEs (immune-related adverse events) was validated using Decision Curve Analysis (DCA). Both uni/multivariable analysis were accomplished by Chi-square/Fisher's exact tests. The accuracy of the model is verified in the DCA curve.

A total of 274 HBV-related liver cancer patients were enrolled in the study. Predictive models were constructed using three machine learning algorithms to analyze and statistically evaluate clinical characteristics, including immune cell data. The accuracy of the Lasso regression model was 0.864, XGBoost achieved 0.903, and RandomForest reached 0.961. Resampling internal validation revealed that RandomForest had the highest recall rate (AUC = 0.892). Based on machine learning-selected indicators, antiviral therapy and The HBV DNA copy number showed a significant correlation with both the occurrence and severity of irAEs. Antiviral therapy notably reduced the incidence of IRAEs and may modulate these events through regulation of B cells. The DCA model also demonstrated strong predictive performance. Effective control of viral load through antiviral therapy significantly mitigates the occurrence of irAEs.

ICIs show therapeutic potential in the treatment of HBV-HCC. Following antiviral therapy, the incidence of severe irAEs decreases. Even in cases where viral load control is incomplete, continuous antiviral treatment can still mitigate the occurrence of irAEs.

Hepatocellular carcinoma (HCC) is a well-known inflammation-related cancer, that accounts for fifth most prevalent neoplasm and the third major driver of cancer associated fatality globally. Accumulating evidence has elucidated that C-X-C motif chemokine ligands (CXCLs) are aberrantly upregulated in HCC and are involved in inflammation-induced hepatocarcinogenesis and metastasis. Herein, we identified a novel function of DEAD-box RNA helicase 17 (DDX17) as an oncogenic factor via transactivating CXCL8 in HCC. Unlike the adjacent nontumor tissues, DDX17 was highly expressed in tumor tissues compared in two independent cohorts and that it acts as an independent prognostic indicator for patients who have HCC. Mechanistically, DDX17 interacts with β-catenin and NF-κB, and promotes their nuclear translocation to promote the transcription of the inflammatory gene CXCL8, thus promoting HCC proliferation and invasion in vitro and in vivo. More interestingly, stimulation with recombinant human CXCL8 augmented the interaction of NF-κB with DDX17/β-catenin and enhanced its autocrine activation by promoting the phosphorylation of IκBα. Furthermore, blocking the association of the DDX17/β-catenin/NF-κB complex with a CXCR1/2 inhibitor markedly abrogated DDX17-mediated HCC proliferation and metastasis. Overall, this study provided new insights into DDX17-mediated pro-inflammatory chemokine activation, which unveiled the association between DDX17 and β-catenin/ NF-κB complex in transactivating the expression of CXCL8. The usage of CXCR1/2 inhibitor to block DDX17-induced CXCL8 signaling activation might be a potential therapeutic approach for HCC treatment.

Hepatocellular carcinoma (HCC) is a significant global health concern, with chronic hepatitis B virus (HBV) infection being a major contributor. Understanding the mechanisms of HBV-associated HCC is crucial to improving the prognosis and developing effective treatments.

HBV-associated HCC datasets (GSE19665, GSE121248, GSE55092, GSE94660, and TCGA-LIHC) acquired from public databases were mined to identify key driver genes by differentially expressed gene analysis, weighted gene co-expression network analysis (WGCNA), followed by protein-protein interaction network analysis, Lasso-Cox regression analysis, and randomforestSRC algorithm. Then, in vitro experiments including CCK-8 assay, wound healing, and Transwell assay were performed to explore the functions and mechanisms.

RAD51AP1 was identified as a specific key gene linked to the progression of HBV-associated HCC. High expression of RAD51AP1 was associated with worse overall survival (OS) in patients with HBV-associated HCC, but not in patients with non-HBV-associated HCC. Mechanistically, RAD51AP1 forms a potential ceRNA axis with LINC01419 and miR-8070, where LINC01419 acts as a molecular sponge for miR-8070 to upregulate RAD51AP1. HBV infection can enhance the LINC01419/miR-8070/RAD51AP1 axis, and LINC01419 overexpression conversely promotes HBV replication. The ceRNA axis and HBV synergistically promote the proliferation and metastasis of HBV-associated HCC cells. Furthermore, LINC01419 or RAD51AP1 knockdown, and miR-8070 overexpression in HepG2.2.15 cells significantly attenuated the Wnt/β-catenin signaling.

The LINC01419/miR-8070/RAD51AP1 axis promotes the HBV-associated HCC progression through an HBV-boosted positive feedback loop and Wnt/β-catenin signaling. These findings provide novel insights into the underlying mechanisms and may offer potential diagnostic and therapeutic targets in HBV-associated HCC.

Emerging evidence indicates a robust association between internal RNA N7-methylguanosine (m7G) modification and hepatocarcinogenesis. However, the precise implications of altered internal m7G modifications within mRNA on the progression of Hepatitis B Virus (HBV)-induced Hepatocellular Carcinoma (HCC) remain inadequately elucidated.

This study utilized a previously published dataset from the Gene Expression Omnibus (GEO) that includes samples of normal liver tissue, HBV positive (HP) liver tissue, and HP HCC tissue to investigate the profiling of mRNA internal m7G methylation. The STRING database and in vitro experiments were employed for the screening and validation of key m7G-related genes. The Cancer Genome Atlas cohorts were utilized to analyze the association of these key genes with the prognosis of HCC patients.

Comparative analyses revealed internal m7G modification alterations in 1546 mRNAs between HP liver and normal liver tissues, and in 3424 mRNAs between HP HCC and HP liver tissues. Following Protein-Protein Interaction (PPI) network analyses, validation experiments confirmed sustained high levels of internal m7G methylation modifications in EZH2, SMARCA4, and YY1. Furthermore, these genes were found to exhibit m7G modification-dependent expression changes during the transition from HBV infection to HCC, and were closely associated with the prognosis of HCC patients.

This study provides validation of substantial dynamic alternations in mRNA internal methylation profiles during the HBV infection to HCC. EZH2, SMARCA4, and YY1 emerge as promising molecular targets within this intricate regulatory landscape, offering avenues for further research and potential therapeutic exploration.

The integration of artificial intelligence (AI) into hepatology is revolutionizing the diagnosis and management of liver diseases amidst a rising global burden of conditions like metabolic-associated steatotic liver disease (MASLD). AI harnesses vast datasets and complex algorithms to enhance clinical decision making and patient outcomes. AI's applications in hepatology span a variety of conditions, including autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, MASLD, hepatitis B, and hepatocellular carcinoma. It enables early detection, predicts disease progression, and supports more precise treatment strategies. Despite its transformative potential, challenges remain, including data integration, algorithm transparency, and computational demands. This review examines the current state of AI in hepatology, exploring its applications, limitations, and the opportunities it presents to enhance liver health and care delivery.

Hepatocellular carcinoma (HCC), characterized by significant morbidity and mortality rates, poses a substantial threat to human health. The expression of ligands and receptors within the classical and non-classical Wnt signaling pathways plays an important role in HCC. The Wnt signaling pathway is essential for regulating multiple biological processes in HCC, including proliferation, invasion, migration, tumor microenvironment modulation, epithelial-mesenchymal transition (EMT), stem cell characteristics, and autophagy. Molecular agents that specifically target the Wnt signaling pathway have demonstrated significant potential for the treatment of HCC. However, the precise mechanism by which the Wnt signaling pathway interacts with HCC remains unclear. In this paper, we review the alteration of the Wnt signaling pathway in HCC, the mechanism of Wnt pathway action in HCC, and molecular agents targeting the Wnt pathway. This paper provides a theoretical foundation for identifying molecular agents targeting the Wnt pathway in hepatocellular carcinoma.

The incidence of liver cancer has shown different temporal trends across populations, while the underlying reasons remain unclear.

We examined temporal trends in the incidence of liver cancer in Hong Kong, Sweden, and the United States since the 1970s through 2021 using joinpoint regression and age-period-cohort analysis.

The age-standardized incidence rate of liver cancer in Hong Kong steadily decreased (average annual percentage change [AAPC] -2.2%, 95% confidence interval [CI] -2.8% to -1.7% in men; AAPC -2.1%, 95% CI -3.1% to -1.1% in women) in 1983-2020. The rate in Sweden increased on average by 0.8% (95% CI 0.2%-1.4%) per year in men and was stable in women (AAPC 0.2%, 95% CI -0.9%-1.4%) in 1970-2021. The rate in the United States increased by 2.1% (95% CI 1.5%-2.8%) per year in men and by 2.1% (95% CI 1.6%-2.5%) in women in 1975-2020, but decreasing trends were noted in 2015-2020 (AAPC -6.6%, 95% CI -8.3% to -4.9% in men; AAPC -4.2%, 95% CI -7.5% to -0.8% in women). Stratified analysis by histological type showed such decrease in recent years was limited to hepatocellular carcinoma, rather than intrahepatic cholangiocarcinoma. We observed distinct changes in trends across age groups and different trends across birth cohorts.

The incidence of liver cancer has decreased in Hong Kong but increased in Sweden and in the United States since the 1980s, despite the decreasing incidence in the United States since 2015. Such disparities may be explained by different etiology and implementation of preventive measures across populations.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), has a significantly higher risk of recurrence. However, the exact mechanism by which HBV prompts HCC recurrence remains largely unknown. In this study liver microarray test revealed significant upregulation of microtubule associated protein 1S (MAP1S) in metastatic HCC compared to control. MAP1S knockdown suppressed growth of HCCLM3 cells in vitro and in vivo. Mechanistically, HBV-encoded X protein (HBx) upregulates MAP1S, which enhances microtubule (MT) acetylation by promoting the degradation of histone deacetylase 6 (HDAC6), and facilitates the nuclear translocation of Smad complex, and thereby enhancing downstream TGF-β signaling. Smad complex, in turn, increases MAP1S, establishing a feedback loop of MAP1S/Smad/TGF-β1. Finally, survival analysis of 150 HBV-associated HCC patients demonstrated both increased MAP1S and decreased HDAC6 were significantly associated with shorter relapse-free survival. Collectively, this study reveals a unique mechanism whereby HBx-induced upregulation of MAP1S drives HBV-related HCC proliferation and migration through the MAP1S/Smad/TGF-β1 feedback loop. TEASER: MAP1S is a key link between HBV infection and a higher risk of metastatic recurrence of HCC.

Liver cancer, the sixth most frequently occurring cancer in the world and the third most common cause of cancer mortality, has wide geographical variation in both incidence and mortality rates. At the end of the 20th century, incidence rates began declining in some high-rate areas and increasing in some lower-rate areas. These trends were undoubtedly driven by the shifting contributions of both well-established and more novel risk factors. While notable strides have been made in combating some major risk factors, such as hepatitis B virus and hepatitis C virus, the emergence of metabolic conditions as important drivers of liver cancer risk indicates that much work remains to be done in prevention. As liver cancer is strongly associated with economic and social deprivation, research, early-diagnosis, and treatment among disadvantaged populations are of paramount importance.

Liver cancer, particularly hepatocellular carcinoma (HCC), poses a significant global health challenge due to its high mortality rate. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) are the two main types of primary liver cancer (PLC), each with its own set of complexities. Secondary or metastatic liver cancer is more common than PLC. It is frequently observed in malignancies such as colorectal, pancreatic, melanoma, lung, and breast cancer. Liver cancer is often diagnosed at an advanced stage, making it difficult to treat. This highlights the need for focused research on early detection and effective treatment strategies. This review explores the epidemiology, risk factors, and diagnostic techniques for HCC. The development of HCC involves various risk factors, including chronic liver diseases, hepatitis B and C infections, alcohol consumption, obesity, smoking, and genetic predispositions. Various invasive and non-invasive diagnostic techniques, such as biopsy, liquid biopsy, and imaging modalities like ultrasonography, computed tomography scans (CT scans), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans, are utilized for HCC detection and monitoring. Advances in imaging technology and biomarker research have led to more accurate and sensitive methods for early HCC detection. We also reviewed advanced research on emerging techniques, including next-generation sequencing, metabolomics, epigenetic biomarkers, and microbiome analysis, which show great potential for advancing early diagnosis and personalized treatment strategies. This literature review provides insights into the current state of liver cancer diagnosis and promising future advancements. Ongoing research and innovation in these areas are essential for improving early diagnosis and reducing the global burden of liver cancer.

Despite superior outcomes with liver transplantation, cirrhotic patients with HCC may turn to other forms of definitive treatment. To understand perioperative outcomes, we examined perioperative mortality and major morbidity after hepatectomy for HCC among cirrhotic and non-cirrhotic patients.

ology: The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was queried for liver resection for HCC. Multivariable logistic regression was performed to determine the association between liver texture and risk of major non-infectious morbidity, post-hepatectomy liver failure (PHLF) and 30-day mortality.

From 2014 to 2018, 2203 patients underwent hepatectomy: 58.6 % cirrhotic, 12.8 % fatty and 28.6 % normal texture. Overall 30 day-mortality was 2.1 % (n = 46), although higher among fatty liver (2.8 %) and cirrhotic (2.6 %; p = 0.025) patients. The incidence of PHLF was 6.9 %, with hepatectomy type, cirrhosis, and platelet count as major risk factors. Age, resection type, and platelet count were associated with major complications. Trisegmentectomy and right hepatectomy (OR = 3.60, OR = 3.46, respectively) conferred a greater risk of major noninfectious morbidity compared to partial hepatectomy. Among cirrhotics alone, hepatectomy type, platelet count, preoperative sepsis and ASA class were associated with major morbidity.

Hepatic parenchymal disease/texture and function, presence of portal hypertension, and the extent of the liver resection are critical determinants of perioperative risk among HCC patients.

The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes‑associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1‑targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.

The association between fiber or whole grain intakes and the risk of liver cancer remains unclear. We assessed the associations between fiber or whole grain intakes and liver cancer risk among 2 prospective studies, and systematically reviewed and meta-analyzed these results with published prospective studies.

A total of 111,396 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and 26,085 men from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study were included. Intakes of total fiber and whole grains were estimated from validated food frequency questionnaires. Study-specific HRs and 95% CI with liver cancer risk were estimated using multivariable-adjusted Cox regression. We systematically reviewed existing literature, and studies were combined in a dose-response meta-analysis. A total of 277 (median follow-up = 15.6 y) and 165 (median follow-up = 16.0 y) cases of liver cancer were observed in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, respectively. Dietary fiber was inversely associated with liver cancer risk in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (HR 10g/day : 0.69; 95% CI: 0.55-0.86). No significant associations were observed between whole grain intakes and liver cancer risk in either study. Our meta-analysis included 2383 incident liver cancer cases (7 prospective cohorts) for fiber intake and 1523 cases (5 prospective cohorts) for whole grain intake; combined HRs for liver cancer risk were 0.83 (0.76-0.91) per 10 g/day of fiber and 0.92 (0.85-0.99) per 16 g/day (1 serving) of whole grains.

Dietary fiber and whole grains were inversely associated with liver cancer risk. Further research exploring potential mechanisms and different fiber types is needed.

Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.

The hepatocellular carcinoma (HCC) features a remarkable epidemiological burden, ranking as the third most lethal cancer worldwide. As the HCC-related molecular and cellular complexity unfolds as the disease progresses, the use of a myriad of in vitro models available is mandatory in translational preclinical research setups. In this review paper, we will compile cutting-edge information on the in vitro bioassays for HCC research, (A) emphasizing their morphological and molecular parallels with human HCC; (B) delineating the advantages and limitations of their application; and (C) offering perspectives on their prospective applications. While bidimensional (2D) (co) culture setups provide a rapid low-cost strategy for metabolism and drug screening investigations, tridimensional (3D) (co) culture bioassays - including patient-derived protocols as organoids and precision cut slices - surpass some of the 2D strategies limitations, mimicking the complex microarchitecture and cellular and non-cellular microenvironment observed in human HCC. 3D models have become invaluable tools to unveil HCC pathophysiology and targeted therapy. In both setups, the recapitulation of HCC in different etiologies/backgrounds (i.e., viral, fibrosis, and fatty liver) may be considered as a fundamental guide for obtaining translational findings. Therefore, a "multimodel" approach - encompassing the advantages of different in vitro bioassays - is encouraged to circumvent "model-biased" outcomes in preclinical HCC research.

The aim of this study was to develop an integrated model that combines clinical-radiologic and radiomics features based on gadoxetic acid-enhanced MRI for preoperative evaluating of vessels encapsulating tumour clusters (VETC) patterns in hepatocellular carcinoma (HCC).

This retrospective study encompassed 234 patients who underwent surgical resection. Among them, 101 patients exhibited VETC-positive HCC, while 133 patients displayed VETC-negative HCC. Volumes of interest were manually delineated for entire tumour regions in the arterial phase (AP), portal phase (PP), and hepatobiliary phase (HBP) images. Independent predictors for VETC were identified through least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression analysis, utilising radiomics-AP, PP, HBP, along with 24 imaging features and 19 clinical characteristics. Subsequently, the clinico-radiologic model, radiomics model, and integrated model were established, with a nomogram visualising the integrated model. The performance for VETC prediction was evaluated using a receiver operating characteristic curve.

The integrated model, composed of 3 selected traditional imaging features (necrosis or severe ischemia [OR=2.457], peripheral washout [OR=1.678], LLR_AP (Lesion to liver ratio_AP) [OR=0.433] and radiomics-AP [OR=2.870], radiomics-HBP [OR=2.023], radiomics-PP [OR=1.546]), showcased good accuracy in predicting VETC patterns in both the training (AUC=0.873, 95% confidence interval [CI]: 0.821-0.925)) and validation (AUC=0.869, 95% CI:0.789-0.950) cohorts.

This study established an integrated model that combines traditional imaging features and radiomic features from gadoxetic acid-enhanced MRI, demonstrating good performance in predicting VETC patterns.

The incidence of tumors in the human digestive system is relatively high, including esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal cancer. These malignancies arise from a complex interplay of environmental and genetic factors. Among them, long non‑coding RNAs (lncRNAs), which cannot be translated into proteins, serve an important role in the development, progression, migration and prognosis of tumors. Small nucleolar RNA host gene 16 (SNHG16) is a typical lncRNA, and its relationship with digestive system tumors has been widely explored. The prevailing hypothesis suggests that the principal molecular mechanism of SNHG16 in digestive system tumors involves it functioning as a competitive endogenous RNA that interacts with other proteins, regulates various genes and influences a downstream target molecule. The present review summarizes recent research on the relationship between SNHG16 and numerous types of digestive system cancer, encompassing its biological functions, underlying mechanisms and potential clinical implications. Furthermore, it outlines the association between SNHG16 expression and pertinent risk factors, such as smoking, infection and diet. The present review indicated the promise of SNHG16 as a potential biomarker and therapeutic target in human digestive system cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings.

A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-β, IL-1β, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence.

Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-β in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them.

Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Circular RNAs (circRNAs) have been identified in diverse cancers for their role in regulating multiple cellular processes by antagonizing microRNAs (miRNAs or miRs). However, the role of circRNA hsa_circ_0000092 in hepatocellular carcinoma (HCC) still remains enigmatic. Therefore, we aimed to investigate the specific mechanism of hsa_circ_0000092 in HCC. Differentially expressed circRNAs associated to HCC were initially analysed. The expression of hsa_circ_0000092, miR-338-3p and HN1 in HCC tissues and cell lines was examined. Next, the interaction among hsa_circ_0000092, miR-338-3p and HN1 was determined by dual-luciferase reporter, RNA pull-down and northern blot assays. Subsequently, a series of mimic, inhibitor or siRNA plasmids were delivered into HCC cells to validate the effects of hsa_circ_0000092, miR-338-3p and HN1 in controlling cell proliferation, migration, invasion and angiogenesis in vitro. Furthermore, the role of hsa_circ_0000092 in tumour growth of HCC in vivo was assessed with hsa_circ_0000092 depleted with siRNA. The hsa_circ_0000092/miR-338-3p/HN1 axis was predicted to participate in the development of HCC. hsa_circ_0000092 and HN1 were highly expressed while miR-338-3p was poorly expressed in HCC tissues and cell lines. hsa_circ_0000092 could competitively bind to miR-338-3p to up-regulate HN1 expression. Moreover, depleted hsa_circ_0000092 or elevated miR-338-3p was shown to suppress HCC cell proliferation, migration, invasion and angiogenesis in vitro via down-regulation of HN1. Furthermore, silencing hsa_circ_0000092 was demonstrated to suppress tumour growth in HCC in vivo. The results of this study suggested that hsa_circ_0000092 impaired miR-338-3p-mediated HN1 inhibition to aggravate the development of HCC, indicating that hsa_circ_0000092 is a potential candidate marker and therapeutic target for HCC.

Liver transplantation (LT) provides a favorable outcome for patients with hepatocellular carcinoma (HCC) and was launched in Vietnam in 2004. In this study, we evaluated the short-term and long-term outcomes of LT and its risk factors.

This retrospective study analyzed HCC patients who underwent LT at Viet Duc University hospital, Vietnam, from 01/2012-03/2022. The following data were gathered: demographics, virus infection, tumor characteristics, alpha-fetoprotein (AFP) level, Child-Pugh and MELD scores, selection criteria, type of LT, complications, 30-day mortality, and disease-free and overall survival (DFS and OS).

Fifty four patients were included, the mean age was 55.39 ± 8.46 years. Nearly 90% had hepatitis B virus-related HCC. The median (interquartile range) AFP level was 16.2 (88.7) ng/mL. The average MELD score was 10.57 ± 5.95; the rate of Child-Pugh A and B were 70.4% and 18.5%, respectively. Nearly 40% of the patients were within Milan criteria, brain-dead donor was 83.3%. Hepatic and portal vein thrombosis occurred in 0% and 1.9%, respectively; hepatic artery thrombosis 1.9%, biliary leakage 5.6%, and postoperative hemorrhage 3.7%. Ninety-day mortality was 5.6%. Five-year DFS and OS were 79.3% and 81.4%, respectively. MELD score and Child-Pugh score were predictive factors for DFS and OS (p < 0.05). In multivariate analysis, Child-Pugh score was the only significant factor (p < 0.05).

In Vietnam, LT is an effective therapy for HCC with an acceptable complication rate, mortality rate, and good survival outcomes, and should be further encouraged.

Previous metabolic profiling of liver cancer has mostly used untargeted metabolomic approaches and was unable to quantitate the absolute concentrations of metabolites. In this study, we examined the association between the concentrations of 186 targeted metabolites and liver cancer risk using prediagnostic plasma samples collected up to 14 years prior to the clinical diagnosis of liver cancer.

We conducted a nested case-control study (n = 322 liver cancer cases, n = 322 matched controls) within the Shanghai Men's Health Study. Conditional logistic regression models adjusted for demographics, lifestyle factors, dietary habits, and related medical histories were used to estimate the odds ratios. Restricted cubic spline functions were used to characterise the dose-response relationships between metabolite concentrations and liver cancer risk.

After adjusting for potential confounders and correcting for multiple testing, 28 metabolites were associated with liver cancer risk. Significant non-linear relationships were observed for 22 metabolites. The primary bile acid biosynthesis and phenylalanine, tyrosine and tryptophan biosynthesis were found to be important pathways involved in the aetiology of liver cancer. A metabolic score consisting of 10 metabolites significantly improved the predictive ability of traditional epidemiological risk factors for liver cancer, with an optimism-corrected AUC increased from 0.84 (95% CI: 0.81-0.87) to 0.89 (95% CI: 0.86-0.91).

This study characterised the dose-response relationships between metabolites and liver cancer risk, providing insights into the complex metabolic perturbations prior to the clinical diagnosis of liver cancer. The metabolic score may serve as a candidate risk predictor for liver cancer.

National Key Project of Research and Development Program of China [2021YFC2500404, 2021YFC2500405]; US National Institutes of Health [subcontract of UM1 CA173640].

Hepatocellular carcinoma (HCC) is an aggressive malignancy that poses a serious threat to human life. The conventional therapies for HCC cannot substantially improve overall survival (OS), disease duration, and prognosis. Therefore, it is important to study the underlying mechanism of HCC and seek better methods for HCC prevention and treatment. Ubiquitination is a post-translational modification that modulates great cellular function by cooperating with E1, E2, and E3 ligases. Yet, the ubiquitination and lysine residues in HCC are still elusive. Seven in absentia homolog 1 (SIAH1), as an important E3 ubiquitin ligase, regulates ubiquitin-mediated proteolysis to function as a tumor suppressor in HCC. In the present study, we downregulated SIAH1 in the mouse HCC cell line Hepa1-6 and studied its function by using proteome-wide identification.

SIAH1 was knocked down by SIAH1 short hairpin RNA (shRNA) in mouse HCC cell line Hepa1-6 cells, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was conducted to analyze the ubiquitinated proteins. Functional analysis was performed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment.

The systematic profiling showed a total of 550 differently expressed proteins (DEPs), including 263 upregulated DEPs and 287 downregulated DEPs. Considering the amino acid sequences around the modified lysine residues, seven proteins were identified as conserved ubiquitination motifs in the peptides. The ubiquitinated proteins were mainly distributed in the cytoplasm, nucleus, and plasma membrane. Functional analysis suggested that the ubiquitinated proteins were mostly enriched in the nucleus, cytoplasm, and extracellular space; in addition, the ubiquitinated proteins were mostly attributed to the protein binding, and disease. The ubiquitinated proteins modulate HCC by mapping lysine modification sites.

The use of high-throughput characterization to identify novel and specific targets associated with SIAH1 is of great significance in terms of functional weight. The results obtained in this paper from the analysis of proteomic data provided novel insights into ubiquitination regulation in HCC, which pave the way for further research and mechanism discovery of HCC.

Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.

Chronic infection with hepatitis B or C substantially increases risk of hepatocellular carcinoma. However, central cancer registries do not routinely collect information on hepatitis diagnoses. We evaluated the extent to which information on hepatitis B or C diagnosis could be ascertained from linked external data sources for cancers reported to the New York State Cancer Registry.

We linked data for 14,747 New York City (NYC) residents diagnosed with liver or intrahepatic bile duct cancer during 2004-2018 to 2 data sources: (1) the NYC Viral Hepatitis Surveillance Registry, which collects information on reported probable and confirmed cases of hepatitis B and C from New York laboratories and health care providers, and (2) the New York Statewide Planning and Research Cooperative System (SPARCS), which captures hepatitis diagnosis codes from hospital inpatient stays and outpatient encounters. We determined whether documentation of hepatitis B or C was present in 1 or both data sources, assessed concordance between the data sources, and used multivariable-adjusted logistic regression to examine factors associated with discordance in hepatitis positivity.

Of the 14,747 cancer cases included, 3,972 had documentation in either data source of hepatitis B (26.9%), 7,599 had documentation of hepatitis C (51.5%), and 9,753 had either diagnosis (66.1%). There was moderate to substantial agreement between the 2 data sources. The percent of NYC patients with any unrecorded hepatitis infection was 12.7% for the hepatitis registry and 7.8% for SPARCS, and discordance in hepatitis positivity was more common in certain individuals, including those aged ≥70 years at cancer diagnosis and those with intrahepatic bile duct cancer, Hispanic ethnicity (hepatitis registry only), and Black or Asian race (SPARCS only).

These results indicate that hospital discharge and public health surveillance data can be used to assess individual-level hepatitis B and C infection status in people diagnosed with liver cancer. Possible reasons for discrepancies between the data sources include incomplete reporting in the hepatitis registry, especially for earlier diagnosis years, differing case inclusion criteria, and differences in the linkage methods for the 2 data sources. This information can be used to enrich cancer registry data for epidemiologic analyses of hepatocellular carcinoma and other cancers.

Liver cirrhosis remains a significant global public health concern, with liver transplantation standing as the foremost effective treatment currently available. Therefore, investigating the pathogenesis of liver cirrhosis and developing novel therapies is imperative. Mitochondrial dysfunction stands out as a pivotal factor in its development. This study aimed to elucidate the relationship between mitochondria dysfunction and liver cirrhosis using bioinformatic methods to unveil its pathogenesis. Initially, we identified 460 co-expressed differential genes (co-DEGs) from the GSE14323 and GSE25097 datasets, alongside their combined datasets. Functional analysis revealed that these co-DEGs were associated with inflammatory cytokines and cirrhosis-related signaling pathways. Utilizing weighted gene co-expression network analysis (WCGNA), we screened module genes, intersecting them with co-DEGs and oxidative stress-related mitochondrial genes. Two algorithms (least absolute shrinkage and selection operator (LASSO) regression and SVE-RFE) were then employed to further analyze the intersecting genes. Finally, COX7A1 and IFI27 emerged as identifying genes for liver cirrhosis, validated through a receiver operating characteristic (ROC) curve analysis and related experiments. Additionally, immune infiltration highlighted a strong correlation between macrophages and cirrhosis, with the identifying genes (COX7A1 and IFI27) being significantly associated with macrophages. In conclusion, our findings underscore the critical role of oxidative stress-related mitochondrial genes (COX7A1 and IFI27) in liver cirrhosis development, highlighting their association with macrophage infiltration. This study provides novel insights into understanding the pathogenesis of liver cirrhosis.

The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.

There have been no reports of acute-on-chronic liver failure (ACLF) during treatment of chronic hepatitis C (CHC) with direct-acting antivirals (DAAs).

We report a 50-year-old male patient with CHC. The patient sought medical attention from the Department of Infectious Diseases at our hospital due to severe yellowing of the skin and sclera, which developed 3 mo previously and attended two consecutive hospitals without finding the cause of liver damage. It was not until 1 mo ago that he was diagnosed with CHC at our hospital. After discharge, he was treated with DAAs. During treatment, ACLF occurred, and timely measures such as liver protection, enzyme lowering, anti-infective treatment, and suppression of inflammatory storms were implemented to control the condition.

DAA drugs significantly improve the cure rate of CHC. However, when patients have factors such as autoimmune attack, coinfection, or unclear hepatitis C virus genotype, close monitoring is required during DAA treatment.

Hepatocellular carcinoma (HCC), the main primary liver cancer, accounts for 5 % of all incident cases and 8.4 % of all cancer-related deaths worldwide. HCC displays a spectrum of environmental risk factors (viral chronic infections, aflatoxin exposure, alcoholic- and nonalcoholic fatty liver diseases) that result in molecular complexity and heterogeneity, contributing to a rising epidemiological burden, poor prognosis, and non-satisfactory treatment options. The emergence of HCC (i.e., hepatocarcinogenesis) is a multistep and complex process that addresses many (epi)genetic alterations and phenotypic traits, the so-called cancer hallmarks. "Polymorphic microbiomes", "epigenetic reprogramming", "senescent cells" and "unlocking phenotypic plasticity" are trending hallmarks/enabling features in cancer biology. As the main molecular drivers of HCC are still undruggable, chemically induced in vivo models of hepatocarcinogenesis are useful tools in preclinical research. Thus, this narrative review aimed at recapitulating the basic features of chemically induced rodent models of hepatocarcinogenesis, eliciting their permanent translational value regarding the "classic" and the "new" cancer hallmarks/enabling features. We gathered state-of-art preclinical evidence on non-cirrhotic, inflammation-, alcoholic liver disease- and nonalcoholic fatty liver-associated HCC models, demonstrating that these bioassays indeed express the recently added hallmarks, as well as reflect the interplay between classical and new cancer traits. Our review demonstrated that these protocols remain valuable for translational preclinical application, as they recapitulate trending features of cancer science. Further "omics-based" approaches are warranted while multimodel investigations are encouraged in order to avoid "model-biased" responses.

Hepatocellular carcinoma (HCC), the fourth most common cancer in Africa, has a dismal overall survival of only 3 months like in sub-Saharan Africa. This is affected by the low gross domestic product and human development index, absence of coherent guidelines, and other factors.

An open forum for HCC-experienced health care workers from Africa and the rest of the world was held in October 2021. Participants completed a survey to help assess the real-life access to screening, diagnoses, and treatment in the North and Southern Africa (NS), East and West Africa (EW), Central Africa (C), and the rest of the world.

Of 461 participants from all relevant subspecialties, 372 were from Africa. Most African participants provided hepatitis B vaccination and treatment for hepatitis B and C. More than half of the participants use serum alpha-fetoprotein and ultrasound for surveillance. Only 20% reported using image-guided diagnostic liver biopsy. The Barcelona Clinic Liver Cancer is the most used staging system (52%). Liver transplant is available for only 28% of NS and 3% EW. C reported a significantly lower availability of resection. Availability of local therapy ranged from 94% in NS to 62% in C. Sorafenib is the most commonly used systemic therapy (66%). Only 12.9% reported access to other medications including immune checkpoint inhibitors. Besides 42% access to regorafenib in NS, second-line treatments were not provided.

Similarities and differences in the care for patients with HCC in Africa are reported. This reconfirms the major gaps in access and availability especially in C and marginally less so in EW. This is a call for concerted multidisciplinary efforts to achieve and sustain a reduction in incidence and mortality from HCC in Africa.

Experiences of stigma and discrimination can act as a significant barrier to testing, monitoring, and treatment for hepatitis B virus (HBV). Aboriginal and Torres Strait Islander Australians are a population disproportionately impacted by HBV and yet limited research has explored HBV-related stigma in these communities. To begin preliminary explorations of HBV-related stigma among Aboriginal and Torres Strait Islander people, we interviewed health workers about their perceptions regarding HBV infection and HBV-related stigma.

Participants were recruited from staff involved in the Deadly Liver Mob (DLM) program which is a health promotion program that offers incentives for Aboriginal and Torres Strait Islander clients to be educated on viral hepatitis, recruit and educate peers, and receive screening and treatment for blood-borne viruses (BBVs) and sexually transmissible infections (STIs), and vaccination. Semi-structured interviews were conducted with 11 Aboriginal and Torres Strait Islander and non-Aboriginal or Torres Strait Islander health workers who have been involved in the development, implementation, and/or management of the DLM program within participating services in New South Wales, Australia.

Findings suggest that stigma is a barrier to accessing mainstream health care among Aboriginal and Torres Strait Islander clients, with stigma being complex and multi-layered. Aboriginal and Torres Strait Islander people contend with multiple and intersecting layers of stigma and discrimination in their lives, and thus HBV is just one dimension of those experiences. Health workers perceived that stigma is fuelled by multiple factors, including poor HBV health literacy within the health workforce broadly and among Aboriginal and Torres Strait Islander clients, shame about social practices associated with viral hepatitis, and fear of unknown transmission risks and health outcomes. The DLM program was viewed as helping to resist and reject stigma, improve health literacy among both health workers and clients, and build trust and confidence in mainstream health services.

Health promotion programs have the potential to reduce stigma by acting as a 'one stop shop' for BBVs and STIs through one-on-one support, yarning, and promotion of the HBV vaccine, monitoring for chronic HBV, and treatment (where required).