Background & Aims: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary cancer, exhibit poor prognosis. This study examined temporal trends in mortality due to BTCs and their major subtypes at international, regional, and national levels. Approach & Results: This observational study used the World

Objective: Chronic HBV infection (CHB) exhausts HBV-specific T cells, develops epigenetic imprints that impair immune responses, and limits the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as αPD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) could reverse these epigenetic imprints and enhance ICI efficacy in restoring HBV-specific

Hepatocellular carcinoma (HCC) surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The

BACKGROUND AIMS Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and if NETs induce

Background and Aims: Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with hepatic stellate cells (HSCs) being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Approach and Results:

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes significant healthcare burdens. Early detection of advanced fibrosis and cirrhosis in MASLD is essential due to their unfavourable outcomes. This multi-level random-effects meta-analysis aimed to provide the best evidence for the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE) in detecting

Background and Aims: Recently proposed “Rule-of-Five” criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes. Methods and Results: Patients without prior hepatic decompensation or

Background and Aims: Ambiguous understanding of tumors and the tumor microenvironments (TMEs) hinders accurate diagnosis and available treatment for multifocal hepatocellular carcinoma (HCC) covering intrahepatic metastasis (IM) and multicentric occurrence (MO). Here, we characterized the diverse TMEs of IM and MO identified by whole-exome sequencing (WES) at single-cell resolution. Approach and Results:

Background & Aims: Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT. Approach & Results: Time-of-flight mass cytometry (CyTOF) revealed that macrophages

Background & Aims: Successful treatment of chronic HBV infection remains a great challenge due to the difficulty in inducing efficient immune responses. Here, we investigated the therapeutic potential of DNA vaccination combined with a potent HBV broadly neutralizing antibody (bNAb) targeting the small surface viral antigen. Approach & Results: C57BL/6 mice were transduced with adeno-associated virus

Background and Aims: Cholestatic liver diseases (CLD) are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter

Background and Aims: Alcohol-related liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg2+) deficiency, which can influence the liver disease progression. The mechanisms underlying Mg2+ homeostasis dysregulation in ALD remain elusive. This

Background and Aims: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain

Background and Aims: Primary biliary cholangitis (PBC) is a rare, progressive liver disease. Obeticholic acid (OCA) received accelerated approval for treating patients with PBC in whom ursodeoxycholic acid (UDCA) failed, based on a surrogate endpoint of reduction in alkaline phosphatase. Analysis of the long-term safety extension with 2 external control groups demonstrated a significant increase in

Background: Hepatocellular carcinoma (HCC) recurrence frequently occurs after curative surgery. Histological microvascular-invasion (MVI) predicts recurrence but cannot provide pre-operative prognostication, whereas clinical prediction scores have variable performances. Methods: Recurr-NET, a multimodal multiphasic residual-network random survival forest deep-learning model incorporating pre-operative

Liver cancer is the third leading cause of cancer-related mortality worldwide. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally-occurring small non-coding RNAs play crucial roles in HCC by simultaneously modulating expression of multiple genes in a fine-tuning manner. Significant

Background and aims: Isocitrate dehydrogenase 1 (IDH1)-mutant cholangiocarcinoma (CCA) is a highly lethal subtype of hepatobiliary cancer that is often resistant to immune checkpoint inhibitor therapies. We evaluated the effects of IDH1-mutations in CCA cells on the tumor immune microenvironment and identify opportunities for therapeutic intervention. Approach and results: Analysis of 2,606 human CCA

Background & Aims: Glypican-3 (GPC3) is a promising target for T-cell therapy in hepatocellular carcinoma (HCC). While chimeric antigen receptor (CAR) T cells targeting GPC3 have demonstrated therapeutic efficacy, their effectiveness is limited by challenges such as low persistence and shedding of surface GPC3. Natural T-cell receptors (TCRs) may serve as an alternative, though identifying GPC3-specific

It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC

Objective: Reliable novel non-invasive biomarkers for the diagnosis of advanced liver fibrosis are urgently needed in clinical practice. We aimed to investigate the accuracy of plasma Follistatin-like protein 1 (FSTL-1) in the diagnosis of advanced liver fibrosis in chronic liver diseases. Design: We collected cross-sectional clinical data for a Derivation Cohort (n=86) and a Validation Cohort (n=431)

Background & Aims: The outcome of patients with hepatocellular carcinoma (HCC) who achieved complete response (CR) to immune-checkpoint-inhibitor (ICI)-based systemic therapies is unclear. Approach & Results: Retrospective study of patients with HCC who had CR according to mRECIST to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine.

Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or hepatocellular carcinoma. The latest single-cell and spatial transcriptomics

Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward with most patients presenting with cholestatic liver tests and the highly specific anti-mitochondrial antibody. For decades

Hepatocellular carcinoma (HCC) is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. Clinical traits and RNA-seq of HCC patients in TCGA were used

Background & Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established. Approach & Results: In this multicenter

Background & Aims: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Approach & Results:

Background & Aims: Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin

Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease (MASLD) when alcohol or viral infections are not involved. MASLD encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation, hepatocyte injury, and fibrosis. Previously