Figure 2.

Overview of the role of programmed cell death pathways in ALD. Ethanol promotes ER stress, ROS production in hepatocytes and gut permeability. Gut microbiome derived LPS enters into liver via portal vein, stimulates hepatocytes and Kupffer cells, resulting in production of pro-inflammatory cytokines such as TNFα, IL-1β, IL-6, and MCP-1. These cytokines can induce death receptor signaling, resulting in apoptosis and necroptosis, the mechanism of cell death depends on caspase-8 activity. Necroptotic cells release DAMPs which activate pyroptosis, as well as ER stress driven by ethanol. Ethanol attenuates the protective functions of autophagy in response to chronic exposure and also promotes ferroptosis via ROS production and iron accumulation. Cumulatively, these changes result in lipid accumulation, increased production of pro-inflammatory cytokines and chemokines, hepatocellular injury and death, resulting in a spiraling progression of liver injury. LPS, lipopolysaccharides; TLR4, toll-like receptor 4; TNFα, tumor necrosis factor α; TNFR, TNF receptor; IL, interleukin; DAMPs, damage-associated molecular patterns; ALD, alcohol-associated liver disease; ER, endoplasmic reticulum; ROS, reactive oxygen species; MCP-1, monocyte chemoattractant protein-1.