Figure 1.

Immune dysregulation in MetALD through the interaction of the gut, liver, and adipose organs. The immune dysregulation in MetALD involves hepatocyte death, the adipocyte-liver axis and gut dysbiosis. (1) Chronic alcohol damages the intestinal barrier, increases intestinal permeability, and triggers an immune response. The dysfunctional gut barrier and products released by gut microbiota lead to the transfer of components and metabolites to the liver and initiate an immune reaction through the biliary system and portal vein communicating with the liver via the gut-liver axis [27]. (2) The crosstalk between adipose and liver organs is mediated by various factors, including neurotransmitters, pro-inflammatory cytokines (e.g., TNF, CCL2, IL-6), anti-inflammatory cytokines (e.g., IL-10), miRNAs, extracellular vesicles (EVs), metabolites, and adipocytokines. This crosstalk promotes hepatocyte damage and inflammation in MetALD [38]. (3) Excessive alcohol consumption can lead to various types of hepatocyte death, such as apoptosis, necroptosis, pyroptosis, and ferroptosis. Hepatocyte apoptosis involves the secretion of apoptosis factors that combine with apaf-1 and caspase-9 to form the apoptosome (intrinsic) and cell apoptosis through miR-21 (extrinsic) [50, 51]. Hepatocyte necroptosis involves RIP1 and RIP3 activation and subsequent MLKL phosphorylation, leading to DAMPs [54, 55]. Canonical pyroptosis depends on caspase-1 and is mediated by the NLRP3 inflammasome, inducing the release of proinflammatory cytokines [57]. Noncanonical pyroptosis is activated by LPS and then activates caspase-4/5 and GSDMD, which regulates NF-ĸB signaling [61]. Ferroptosis is an iron-dependent cell death mechanism characterized by glutathione (GSH) depletion and damage to system Xc-, leading to cell death through ROS accumulation and lipid peroxidation [63]. These factors activate mucosal immune cells such as macrophages, NK T cells, KCs, MAIT cells and T cells releasing proinflammatory cytokines and chemokines, ultimately leading to hepatocyte death. MetALD, metabolic dysfunction-associated alcoholic liver disease; CCL2, Chemokine (CC-motif) ligand 2; IL, interleukin; RIP-1/3, receptor interacting protein-1/3; MLKL, mixed lineage kinase domain like; DAMPs, danger associated molecular patterns; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; LPS, lipopolysaccharide; GSDMD, gasdermin D; NFĸB, nuclear factor kappa B; ROS, reactive oxygen species; KCs, Kupffer cells; MAIT, Mucosal Associated Invariant T cells.