Liver sinusoidal microthrombosis (LST) is recognized as an initiating event in fibrogenesis and portal hypertension in chronic liver diseases. Liver sinusoidal endothelial cell (LSEC)-derived chemoattractants recruit neutrophils and macrophages, promoting LST in congestive hepatopathy (CH). However, the driving molecules from LSECs for LST remain unclear. This study aims to elucidate that LSECs inflammatory via cyclooxygenase-2 (COX-2) upregulation triggers metabolic reprogramming promoting thrombospondin-1 (TSP-1)-mediated LST and portal hypertension. A murine model of LST and portal hypertension was established by partial ligation of inferior vena cava (pIVCL). LST and portal hypertension were suppressed in both LSEC-specific COX-2 knockout mice (Ptgs2ΔLSEC) and celecoxib-treated wild-type mice induced by pIVCL. RNA sequencing of mouse liver tissue and untargeted metabolomics of human hepatic sinusoidal endothelial cells (HHSECs) revealed that COX-2 inhibition was concurrent with downregulation of the AKT/mTOR pathway, reduced lactate, and decreased TSP-1. In vitro, COX-2-derived prostaglandin E2 (PGE2) activated the AKT/mTOR pathway, driving glycolytic reprogramming and lactate production. In turn, the accumulation of lactate induced by COX-2 upregulation enhanced histone H3K9 lactylation, which transcriptionally upregulated Thbs1 (encoding TSP-1), thereby instigating a prothrombotic phenotype in LSECs. Collectively, this study uncovers a novel pathogenic axis in LST formation, where COX-2 drives a prothrombotic switch in LSECs via AKT/mTOR-mediated metabolic reprogramming and lactate-dependent epigenetic upregulation of TSP-1. Targeting LSEC COX-2 may represent a promising therapeutic strategy for mitigating LST and portal hypertension.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4-dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation-dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

BACKGROUND The effect of post-transjugular intrahepatic portosystemic shunt (TIPS) rebleeding on liver-related mortality remains uninvestigated. AIM To investigate the relationship between post-TIPS rebleeding and liver-related mortality in patients with cirrhosis and to conduct subgroup analyses based on liver function. METHODS This study included 1782 patients who underwent covered TIPS at seven medical centers to prevent rebleeding. The primary endpoints were liver-related death and all-cause rebleeding. Propensity score matching, adjusted survival curves, and competing risk analyses based on liver transplantation and non-liver death were performed to ensure the robustness of the results. RESULTS During a median follow-up period of 32.25 months, 346 patients (19.4%) developed post-TIPS rebleeding, and 429 (24.1%) died from liver-related causes. Chronic HBV infection was the predominant cirrhosis etiology. Multivariable analysis identified older age, higher Child-Pugh and model for end-stage liver disease-Na scores, and post-TIPS rebleeding as independent predictive factors for liver-related mortality. Liver-related mortality increased by approximately 49.4% in the rebleeding group compared with the no-bleeding group. These findings remained consistent after propensity score matching, survival curve adjustment, and competing risk assessment. Similar findings were observed across different liver function subgroups. CONCLUSION Post-TIPS rebleeding was significantly associated with higher mortality in patients with cirrhosis and variceal bleeding irrespective of liver function category.

Background: Chronic alcohol consumption is a recognized cause of pancreatic steatosis, though its imaging characteristics in individuals remain undefined. This study investigated the effect of chronic alcohol intake on the pancreatic fat content and distribution in a male population and assessed the impact of abstinence. Methods: In this cross-sectional study, 140 male alcohol drinkers (who consumed >20 g ethanol/day for >5 years) and 142 male non-drinkers were recruited. The pancreatic fat fraction (FF) was quantified using T1- and T2*-corrected double-echo chemical shift magnetic resonance imaging (CSI). Participants were stratified by age (20-50 years, 50-70 years). Drinkers were further categorized as current drinkers or short-term (<1 year) or long-term (1-2 years) abstainers. Results: The pancreatic FF was significantly higher in alcohol drinkers compared with age-matched controls in the 20-50-year-old (6.07 ± 1.59% vs. 2.94 ± 0.62%, p < 0.05) and 50-70-year-old (9.14 ± 2.22% vs. 5.98 ± 1.00%, p < 0.05) groups. In drinkers aged 40-70 years, the pancreatic fat distribution was uneven. No significant difference in the FF was observed across the three drinking status groups (p > 0.05). Conclusions: Chronic alcohol consumption could cause fat deposition in the pancreas. An uneven distribution of pancreatic fat began in the fourth decade in this male population. An alcoholic fatty pancreas was not reversed within a follow-up period of up to two years.

ABSTRACT:Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver injuries, including steatosis to steatohepatitis (MASH), liver fibrosis, cirrhosis, and relevant complications. The liver mainly comprises hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), immune cells (T cells, B cells), and hepatic stellate cells (HSCs). Crosstalk among these different liver cells, endogenous aberrant glycolipid metabolism, and altered gut dysbiosis are involved in the pathophysiology of MASLD. This review systematically examines advances in understanding the molecular pathogenesis of MASLD, with a focus on emerging therapeutic targets and translational clinical trials. We first delineate the crucial regulatory mechanisms involving diverse liver cells and the gut-liver axis in MASLD development. These cell-specific pathogenic insights offer valuable perspectives for advancing precision medicine approaches in MASLD treatment. Furthermore, we evaluate potential therapeutic targets and summarize clinical trials currently underway. By comprehensively updating the MASLD pathophysiology and identifying promising strategies, this review aims to facilitate the development of novel pharmacotherapies for this increasingly prevalent condition.

Hepatitis B virus (HBV) remains a major global public health issue, posing significant threats to human health and quality of life. Its treatment has always been the focus of contemporary medicine. Compared with traditional antiviral drugs, pegylated interferon (Peg-IFN), as an important drug for treating chronic hepatitis B (CHB), is expected to achieve functional cure. In addition, IFN has shown definite efficacy and advantages in inhibiting viral replication, improving liver inflammation, and reducing the risk of liver cirrhosis and hepatocellular carcinoma. However, due to significant side effects and poor compliance, IFN faces many challenges. This chapter systematically analyzes the mechanisms underlying IFN therapy as well as current advances in clinical research regarding IFN for the treatment of CHB.

Background There is no effective drug treatment for the organ failure (OF) caused by severe acute pancreatitis (SAP). Objective We aimed to evaluate the efficacy of cyclooxygenase-2 inhibitors (COX-2-Is) on the treatment of SAP and its safety. Design In this multicentre, double-blind, randomised, placebo-controlled, investigator-initiated trial, 348 patients with acute pancreatitis aged 18–75 years, <1 week from onset of illness to admission, and Acute Physiology and Chronic Health Evaluation II Score ≥7 or modified Marshall Score ≥2, were randomly assigned (1:1) to the COX-2-Is group (parecoxib sequential with imrecoxib) or the placebo group. SAP occurrence, duration of OF, local complications, clinical outcomes and serum inflammatory mediators were measured. Results Compared with the placebo group, SAP occurrence was reduced by 20.7% (77.6% vs 61.5%, p=0.001) and the persistent OF duration in SAP was shortened by 2 days (p<0.001) after COX-2-Is treatment. For patients enrolled within or after 48 hours from symptom onset, SAP occurrence was reduced by 23.8% (p=0.001) and 8.5% (p=0.202), and the persistent OF duration in SAP was shortened by 3 days (p=0.001) and 2 days (p=0.010) after COX-2-Is treatment, respectively. The occurrence of local complications in the COX-2-Is group was significantly lower than those in the placebo group, 33.7% vs 49.1%, p=0.004. The serum levels of inflammatory mediators and 30-day mortality (from 8.6% to 3.4%) were significantly reduced after COX-2-Is treatment, p<0.05. The incidence of adverse events was similar between the two treatment groups. Conclusion Parecoxib sequential with imrecoxib was effective and well tolerated in reducing the occurrence and duration of SAP and local complications through suppression of systemic inflammatory response, leading to decreased morbidity.

Background and Aims:Ferroptosis plays an essential role in chronic liver diseases, and cyclooxygenase-2 (COX-2) affects liver fibrosis through multiple mechanisms. However, research on COX-2 regulation of ferroptosis in chronic liver injury remains limited. This study aimed to investigate whether and how COX-2 regulates ferroptosis in chronic liver injury. Methods:In vivo, a thioacetamide (TAA)-induced chronic liver injury model, characterized by significant liver lipid peroxidation and oxidative stress, was used. COX-2 +/+ and COX-2 -/- mice were treated with TAA or normal saline. In vitro, primary mouse hepatocytes were isolated and treated with dimethyl sulfoxide (DMSO), erastin+DMSO, etoricoxib+erastin+DMSO, and tBHQ+erastin+DMSO. Mitochondrial morphology, iron metabolism, lipid peroxidation, and oxidative stress were assessed to verify ferroptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was measured to investigate the relationship between COX-2 and ferroptosis. Results:TAA-treated COX-2 -/- mice presented milder liver fibrosis, whereas TAA-treated COX-2 -/- mice livers and etoricoxib+erastin+DMSO-treated primary hepatocytes exhibited alleviated mitochondrial damage compared with TAA-treated COX-2 +/+ littermates and erastin+DMSO-treated primary hepatocytes, respectively. The knockout of COX-2 decreased ferrous ion concentration (p < 0.01) and mitigated lipid peroxidation in TAA-treated livers (p < 0.05). Furthermore, both COX-2 knockout and etoricoxib restored reduced glutathione (p < 0.05) and glutathione peroxidase 4 (p < 0.05), while decreasing malondialdehyde levels (p < 0.05). Additionally, COX-2 inhibition upregulated Nrf2, which helped alleviate erastin+DMSO-induced ferroptosis (p < 0.01). Conclusions:Ferroptosis contributes to the progression of chronic liver injury. Inhibition of COX-2 upregulates Nrf2, mitigating hepatocyte ferroptosis in chronic liver injury.

BACKGROUND:Transjugular intrahepatic portosystemic shunt (TIPS) is an established procedure for managing portal hypertension in cirrhotic patients, but the impact of post-TIPS overt hepatic encephalopathy (OHE) on survival remains controversial. While its effect on short-term survival is well-documented, its long-term implications remain unclear. AIMS:This study aims to investigate the long-term impact of post-TIPS OHE on mortality in cirrhotic patients for variceal bleeding, focusing on the timing and predictive value of OHE beyond the first year post-TIPS. METHODS:A multicenter, retrospective cohort study was conducted involving 3262 cirrhotic patients who underwent TIPS for variceal bleeding at seven Chinese tertiary centers between January 2010 and June 2020. Clinical data, including demographics, procedure details, post-TIPS complications and survival outcomes, were collected. The primary endpoints were all-cause mortality and OHE, with follow-up until death, liver transplantation or 60 months. Propensity score matching minimised confounding effects, and multivariate Fine-Grey competing risk models identified independent mortality predictors. RESULTS:During a median follow-up of 1077 days, 33.2% developed post-TIPS OHE, associated with higher MELD and Child-Pugh scores. Among these, 19.3% died, with a median time from OHE onset to death of 947 days. Post-TIPS OHE was not linked to early survival (within 12 months) but emerged as an independent predictor of long-term mortality beyond 24 months, consistent across various clinical scenarios. CONCLUSION:Post-TIPS OHE does not affect short-term survival but significantly increases long-term mortality risk. These findings highlight the need for continuous monitoring and tailored interventions to improve long-term outcomes in post-TIPS patients.

INTRODUCTION:Hepatic encephalopathy (HE), a severe complication of decompensated cirrhosis, is characterised as neurocognitive dysfunction. Emerging evidence suggests the potential role of human albumin infusion for the treatment of HE, but its optimal dosage remains undefined. Therefore, we planned a randomised controlled trial (RCT) to compare the efficacy of human albumin infusion at different dosages in patients with liver cirrhosis and overt HE. METHODS AND ANALYSIS:This RCT will be conducted in the Departments of Gastroenterology or Hepatology of 16 tertiary hospitals in China. Overall, 174 patients with a diagnosis of liver cirrhosis, overt HE and a serum albumin level of 23-30 g/L will be enrolled. They will be stratified according to the severity of overt HE and randomly assigned at a ratio of 1:1 into the groups of human albumin infusion at a modified dosage and a routine dosage. The primary end point is the improvement of overt HE within 3-5 days after treatment. The secondary end points include recurrence of overt HE, survival and adverse events. We expect that this RCT will provide high-quality evidence on the optimal dosage of human albumin infused, which can achieve more clinical benefits to patients with liver cirrhosis and overt HE. ETHICS AND DISSEMINATION:The study has been approved by the Medical Ethical Committee of the General Hospital of Northern Theater Command (ethical approval number Y2024-148). The study findings will be published in academic journals. TRIAL REGISTRATION NUMBER:NCT06483737.