Pathophysiological mechanisms of cell death affecting graft survival in liver transplantation

Table 1 Early allograft failure after living donor liver transplantation model

n	Factor
1	MELD score ≥ 27
2	Donor BMI > 30 kg/m2
3	Portal vein thrombosis
4	Hepaticojejunostomy
5	Peak alanine transferase > 468 U/L
6	Peak INR > 1.9
7	Bilirubin > 3.5 mg/dL at 7th postoperative week
8	INR > 1.3 at 7th postoperative week

Early allograft failure in living donor liver transplantation model at the highest risk for EAD: Sensitivity 75.0%, specificity 73.7%. MELD: Model for end-stage liver disease; BMI: Body mass index; INR: International normalized ratio.

Table 2 Model for end-stage liver disease score and need for transplantation

Variables	Calculation score equation	Score clinical relevance
TBIL	MELD: (3.78 × TBIL) + (11.2 × INR) + (9.57 × Cr) + 6.43	15 → transplanta-tion
INR	MELD-Na: MELD + 1.32 × (137-Na)-[0.033 × MELD × (137-Na)]	15-24 → interme-diate priority
Cr (mg/dL)		≥ 25 → high priority
Na		≥ 30 → high risk patient

MELD: Model for end-stage liver disease; TBIL: Total bilirubin; INR: International normalized ratio; Cr: Creatinine; Na: Sodium.

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.

Table 4 Major characteristics of cell death pathways affecting liver graft function in liver transplantation

Cell death pathway	Molecular mediators	Pathophysiological mechanisms	Main features	Clinical consequences
Apoptosis	TNF-R1, DR4 and DR5 receptors, Caspase-8, Caspase-10, Cytochrome c, AIF, Caspase-9, Caspase-3, Bcl-2 family	DISC formation, ATP depletion, oxidative stress, mitochondrial dysfunction, immune cell infiltration	Cell shrinkage, membrane bulging, nuclear fragmentation, DNA reorganization, formation of membrane-bound apoptotic bodies	Hepatocyte loss, HIRI, liver graft dysfunction, EAD
Necrosis	DAMPs, PRRs, TLRs, NLRs, NF-κB activation, ROS	Inflammatory response, loss of mitochondrial membrane potential, ATP depletion, mitochondrial swelling, membrane rupture, oxidative stress, calcium overload	Cellular breakdown, MPTP opening, DAMPs release	HIRI, sterile inflammatory response, EAD, graft rejection
Autophagy	ATG, AMPK/mTOR, PINK1/Parkin, ROS, NLRP3 inflammasome, MAPK	Inflammatory response, energy balance, oxidative stress	Damaged organelles and proteins degradation and recycling, mitophagy	Hepatocellular injury mainly in steatotic or aged liver grafts, graft rejection, EAD
Ferroptosis	Erastin, GPX4, TRPM2, IDO-1, STAT1/STAT3, DAMPs, ROS	TRPM2-dependent calcium influx, IDO-1 activation, overregulation of iron metabolism, oxidative stress, cytokine production, DAMPs release	Iron-dependent lipid peroxidation, GSH depletion, GPX4 inactivation	HIRI, graft rejection, EAD, LSECs and hepatocellular injury
Pyroptosis	Caspase-1, NLRP3, GSDMD, Caspase 4/5, ROS, cGAS-STING, cytokines	DAMPs and PAMPs release, inflammatory response, oxidative stress	Cell edema, membrane rupture, calcium overload	HIRI, DCD and steatotic graft injury, EAD
Necroptosis	RIPK3, DAMPs, MLKL, TNFRSF, TLR3/TLR4, interferon receptors, ROS, cytokines	Oxidative stress, inflammatory response, necrosome formation	Membrane rupture, DAMPs release	HIRI, hepatocellular injury, EAD and graft rejection
PANoptosis	PANoptosome, ZBP1, NLRP3, RIPK1, RIPK3, caspase-6, caspase-8, caspase-1, AIM2, ASC, FADD, cytokines, ROS	Severe inflammatory response, oxidative stress	Combined activation of pyroptosis, apoptosis and necroptosis	HIRI, steatotic graft injury
NETosis	ROS, NE, MPO, PAD4, GSDMD, DAMPs	Neutrophil activation, sterile inflammatory response, DAMPs release, platelets aggregation	Nuclear membrane disruption and DNA release, NETs formation	Graft injury, HIRI, microthrombus formation, acute rejection, EAD, arterial thrombosis, hepatocellular carcinoma reccurrence

TNF-R1: TNF-α-receptor; DISC: Death-inducing signaling complex; AIF: Apoptosis-inducing factor; DAMPs: Damage-associated molecular patterns; MPTP: Mitochondrial permeability transition pore; PRRs: Pattern recognition receptors; TLRs: Toll-like receptors; NLRs: NOD-like receptors; NF-κB: Nuclear factor κΒ; ROS: Reactive oxygen species; ATG: Autophagy-related proteins; MAPK: Mitogen-activated protein kinase; GSH: Glutathione; GPX4: Glutathione peroxidase 4; TRPM2: Transient receptor potential melastatin 2; IDO-1: Macrophage-derived indoleamine 2,3-dioxygenase 1; STAT1/STAT3: Signal transducer and activator of transcription; GSDMD: Gasdermin D; DCD: Donation after circulatory death; cGAS-STING: Cyclic GMP-AMP synthase; PAMPs: Pathogen-associated molecular patterns; RIPK3: Receptor-interacting protein kinase 3; MLKL: Mixed lineage kinase domain-like protein; TNFRSF: Tumor necrosis factor receptor superfamily; ZBP1: Z-DNA-binding protein 1; AIM2: Absent in melanoma 2; ASC: Apoptosis-associated speck-like protein containing a CARD; FADD: Fas-associated death domain; NETs: Neutrophil extracellular traps; NE: Neutrophilic elastase; MPO: Myeloperoxidase; PAD4: Peptidyl-arginine deaminase 4; EAD: Early allograft dysfunction; HIRI: Hepatic ischemia-reperfusion injury; LSECs: Liver sinusoidal endothelial cells.