Pathophysiological mechanisms of cell death affecting graft survival in liver transplantation

Table 3 Cell type–specific regulated cell death pathways in liver transplantation

Cell type	Dominant cell death pathway	Key mediators	Clinical implications
Hepatocytes	Apoptosis, necrosis, ferroptosis, autophagy, necroptosis, PANoptosis, pyroptosis	Caspase -3, caspase-8, caspase-9, Bcl-2 family, GPX4, ACSL4, Slc7A11, RIPK1/RIPK3/MLKL, ZBP1, NF-κB, ROS, DAMPs, NLRP3, GSDMD	Hepatocellular injury, elevated transaminases, graft dysfunction, EAD
LSEcs	Ferroptosis, apoptosis, autophagy	GPX4, HO-1, caspase-3, ROS	Endothelial dysfunction, impaired microcirculation, HIRI, EAD
KCs	Apoptosis, pyroptosis, necroptosis, PANoptosis	NLRP3, ASC, caspase-1, GSDMD, RIPK3, MLKL, cytokines, ROS	Cytokine storm, inflammatory response, HIRI
Cholangiocytes	Apoptosis, necrosis	Caspases, oxidative stress mediators	Biliary complications
Infiltrated macrophages	Pyroptosis, necroptosis, ferroptosis	NLRP3, caspase-1, cytokines, ROS	Innate inflammatory activation, HIRI
Neutrophils	NETosis	ROS, NE, MPO, PAD4, GSDMD, DAMPs	HIRI, microthrombus formation, acute rejection, EAD, inflammatory response

LSECs: Liver sinusoidal endothelial cells; KCs: Kupffer cells; GPX4: Glutathione peroxidase 4; ACSL4: Acyl-CoA synthetase long-chain family member 4; RIPK: Receptor-interacting protein kinase; MLKL: Mixed lineage kinase domain-like protein; ZBP1: Z-DNA-binding protein 1; NF-κB: Nuclear factor κB; ROS: Reactive oxygen species; DAMPs: Damage-associated molecular patterns; NLRP3: NLR family pyrin domain containing 3; GSDMD: Gasdermin D; HO-1: Heme oxygenase-1; ASC: Apoptosis-associated speck-like protein containing a CARD; NE: Neutrophilic elastase; MPO: Myeloperoxidase; PAD4: Peptidyl-arginine deaminase 4; EAD: Early allograft dysfunction; HIRI: Hepatic ischemia-reperfusion injury.