Roles of necroptosis in alcoholic liver disease and hepatic pathogenesis

Abstract

Chronic alcohol consumption can cause alcoholic liver disease (ALD), leading to morbidity and mortality worldwide. Complex disease progression of ALD varies from alcoholic fatty liver to alcoholic steatohepatitis, eventually contributing to fibrosis and cirrhosis. Accumulating evidence revealed that necroptosis, a way of programmed cell death different from apoptosis and traditional necrosis, is involved in the underlying pathogenic molecular mechanism of ALD. Receptor‐interacting protein kinase 1 (RIPK1), RIPK3 and mixed‐lineage kinase domain‐like pseudokinase have been implicated as key mediators to execute necroptosis. Also, necroptosis has gained increasing attention due to its potential association with primary pathological hallmarks of ALD, including oxidative stress, hepatic steatosis and inflammation. This review summarizes the recent progress on the roles and mechanisms of necroptosis and focuses on the crosstalk between necroptosis and the other pathogenesis of ALD, providing a theoretical basis for targeting necroptosis as a novel treatment for ALD.

Identification and Validation of Prognostic Model for Pancreatic Ductal Adenocarcinoma Based on Necroptosis-Related Genes

“…Necroptosis is an important programmed cell death, which is characterized by the activation of MLKL/pMLKL by the RIPK1/RIPK3-mediated phosphorylation signal pathway ( Karlowitz and van Wijk 2021 ; Zhou et al, 2022 ). Recent studies have found that NRGs play a dual role in both facilitating and suppressing the progression of different tumor cells and could be used as prognostic and therapeutic biomarkers in patients with many types of tumors ( Pasparakis and Vandenabeele, 2015 ; Li et al, 2020 ).…”

Advancements in the Alcohol-Associated Liver Disease Model

“…The pathways involved in PCD include the apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis pathways [ 19 ]. Apoptosis is a cystein-dependent cell death, and chronic alcohol intake induces oxidative stress, hypoxic stress, and endoplasmic reticulum stress in cells, leading to the activation of endogenous and exogenous apoptosis [ 20 , 21 ]. Cellular stress induces apoptosis in the liver by activating caspase-12/4, the interferon regulatory factor signalling pathway, and the C-Jun N-terminal kinase [ 22 ].…”

“…Ethanol exposure increases intestinal permeability and subsequent entry of LPS into the portal vein circulation, which stimulates resident hepatic macrophages, and infiltrates monocytes to produce inflammatory factors such as tumour necrosis factor -α(TNFα) through the activation of Toll-like receptor 4 (TLR4), thereby activating the exogenous pathway of apoptosis [ 22 ]. Necrosis is a novel form of PCD mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL) [ 21 ]. Necrosis has been shown to play a key role in oxidative stress, steatosis, and inflammatory response in ALD [ 24 , 25 , 26 , 27 ].…”

“…There is increasing evidence that RIPK3 and MLKL have been shown to be regulators of lipid metabolism, controlling hepatic steatosis to varying degrees [ 29 , 30 ]. With alcohol exposure, necrotic cells release danger signals called damage-associated molecular patterns (DAMPs) that trigger and promote inflammatory responses [ 21 ]. Pyroptosis is a newly discovered form of PCD mediated by gasdermin protein and is accompanied by inflammatory and immune responses [ 31 ].…”

Coral Hydrate, a Novel Antioxidant, Improves Alcohol Intoxication in Mice

“…Drinking culture is a worldwide phenomenon, but long-term alcohol consumption may lead to alcoholic fatty liver disease [ 1 ]. In addition to increasing the risk of chronic disease, excessive ethanol intake can cause acute unpleasant physiological and psychological effects, including hangover [ 2 ].…”