Publications by Year: 2025

Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.

BACKGROUND & AIMS: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.

METHODS: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis murine model. Liver, kidney, and brain tissues and behavior were assessed in mice. Livers from patients with sclerosing cholangitis with and without ACLF were also evaluated.

RESULTS: In advanced fibrosis induced by BDL, an alcohol binge induced features of ACLF, including significant liver damage, systemic inflammation (increased endotoxin and pro-inflammatory cytokines), and hepatocyte dysfunction compared with BDL alone. ACLF was associated with extrahepatic manifestations, including increased blood urea nitrogen and creatinine, impaired coagulation, and features of encephalopathy. We discovered significantly increased neutrophil count and neutrophil extracellular traps (NETs) in the liver, kidney, and brain in murine ACLF. Livers from ACLF mice showed increased pyroptosis (gasdermin D) and necroptosis (receptor-interacting protein kinase 3 [RIPK3]), when compared with BDL. In vitro, cell-free NETs were induced by alcohol and/or bile acids and triggered pyro-/necroptotic death in hepatocytes. NETosis, pyroptosis, and RIPK3 activation were validated in human livers with ACLF. Moreover, pharmacological inhibition of necroptosis with a RIPK3 inhibitor-ameliorated inflammation, NETs, and liver fibrosis, improving multi-organ ACLF pathophysiology.

CONCLUSIONS: Our novel ACLF model triggered by alcohol binge mimics key features of pathophysiology and multi-organ impairment in human ACLF. Our results indicate that neutrophil infiltration and NETs contribute to hepatocyte cell death via pyroptosis and necroptosis in ACLF, identifying RIPK3 as a potential therapeutic target.