Table 1.
The characteristics of each programmed cell death pathway in ALD
| Apoptosis | Necroptosis | Autophagy | Pyroptosis | Ferroptosis | |
|---|---|---|---|---|---|
| Morphological features | Cell shrinkage, nucleus fragmentation, membrane blebbing, apoptotic body [7] | Cell swelling, blebs devoid of organelles, release of DAMPs [4,11,12] | Accumulation of double-membraned autophagic vacuoles [21-23] | Cell swelling, osmotic lysis, release of DAMPs, IL-1β and IL-18 [30-32] | Electron-dense mitochondria, rupture the outer mitochondrial membrane, the presence of lipid peroxidation. |
| Release of DAMPs [36] | |||||
| Trigger | ER stress, ROS, hypoxia [5,9,10] | ER stress, ROS, hypoxia [5,19,20] | ER stress, ROS, hypoxia [21-23] | PAMPs, DAMPs, ER stress [30-33] | Iron accumulation, ROS, ER stress [36,37,42,43] |
| Key proteins | Initiation (caspase-2, -8, -9, and -10), execution (caspase -3, -6, and -7) Bcl-2, FADD [7-9] | RIP1, RIP3, and MLKL [5,12,19,20] | ULK 1 kinase complex, class III PI3K complex, ATG5, ATG7, LC3, mTORC1, [21-23] TFEB [24,27] | GSDMD, inflammasomes, caspase 1/4/5/11, IL-1β and IL-18 [30-32] | GSH, GPX4, [37,45] hepcidin [42-44] |
| Hepatocyte | ROS, ER stress, CYP2E1 cause apoptosis in mitochondria. | The activation of RIP1-RIP3-MLKL axis cause necroptosis under caspase-8 inhibition. [5,19-20] | Macrophagy deletes unfolded protein. [21] Lipophagy reduces the accumulation of lipids. [21] | Activated inflammasomes actlvate caspase 1/11, which mature GSDMD and pro-, IL-1β and pro-IL-18, resulting in release of DAMPs, IL-1β and IL-18 [30-32] | Reactive hydroxyl radical by iron accumulation injures lipid membranes to induce lipid peroxidation and membrane instability, which can ultimately result in leakage of cellular material and cell death. [38-43] |
| TNFα signal induced caspase-8 results in apoptosis. [4,5,10] | |||||
| The role in or to immune cells | Kupffer cells produce TNFα by LPS-TLR4 signal activation from leakage-gut. [5] | Immune cells are activated by DAMPs released from necroptotic hepatocytes [5,14-16] | Autophagy plays a role of anti-inflammatory response and anti-steatosis via cannabinoid receptor 2 in Kupffer cells. [28] | DAMPs, IL-1β and IL-18 by pyroptosis recruit and activate macrophages, neutrophils and lymphocytes to produce pro-inflammatory cytokines. [5,30-32,34] | Loss of iron in macrophage stores via lowhepcidin by ethanol consumption results in hyperabsorption of iron [44] |
| Role in ALD | Promote | Promote | Suppress | Promote | Promote |
ALD, alcohol-associated liver disease; DAMPs, damage-associated molecular patterns; IL, interleukin; ER, endoplasmic reticulum; ROS, reactive oxygen species; PAMPs, pathogen-associated molecular patterns; FADD, FAS associated death domain protein; RIP, receptor interacting protein; MLKL, mixed lineage kinase domain like pseudokinase; PI3K, phosphatidylinositol 3-kinase; ATG, autophagy-related genes; LC3, light chain 3; mTORC1, mTOR complex 1; TFEB, transcription factor EB; GSDMD, gasdermin D; GSH, glutathione; GPX4, glutathione peroxidase-4; TNFα, tumor necrosis factor α; LPS, lipopolysaccharides; TLR4, toll-like receptor 4.