. Author manuscript; available in PMC: 2022 May 3.

Published in final edited form as: Dev Cell. 2021 Apr 21;56(9):1221–1233. doi: 10.1016/j.devcel.2021.03.033

Table 1.

Key aspects of regulated cell-death pathways

RCD	Inducer	Mediator	Amplifier	Effector	Phenotype

Apoptosis (extrinsic)	DRs	DISC	CASP-8/-10 (sometimes MOMP)	CASP-3/-6/-7	organelle breakdown, condensed nucleus, cleaved DNA, apoptotic bodies
Apoptosis (intrinsic)	DNA damage, metabolic stress	BCL-2 family	MOMP, apoptosome, CASP-9	CASP-3/-6/-7	organelle breakdown, condensed nucleus, cleaved DNA, apoptotic bodies
Entosis	loss of cell-matrix interactions	Cell-cell junctions	actin, actomyosin	LAP machinery	engulfment by non-phagocytic neighbor
Ferroptosis	cystine starvation, x_c⁻ inhibition	GSH depletion, GPX4 exhaustion	LOXs, ROS	PUFA peroxides, aliphatic aldehydes	necrotic, mitochondria alterations (shrinkage, rupture, disordered cristae)
MPT-Driven necrosis	cytosolic Ca²⁺, oxidative damage	mPTP containing cyclophilin D	increased IMM permeability	OMM rupture	necrotic, mitochondrial swelling and rupture
NETosis	activation-induced ROS production	NADPH oxidase complex, ROS, H₂O₂	MPO	elastase	DNA decondensation, membrane degradation, NET release
Necroptosis	DRs, PRRs	DISC/RIP1, TRIF, inhibited CASPs	RIP3	MLKL pore, ATP depletion?	necrotic (cell swelling, membrane rupture, DAMP release)
Oxytosis	glutamate overload, cystine starvation	GSH depletion, GPX4 deficiency	LOXs, ROS, Ca²⁺ influx	calpains, AIF, PUFA peroxides	necrotic, mitochondria alterations (shrinkage, rupture, disordered cristae)
Parthanatos	DNA damage, ROS, increased Ca²⁺	PARP1	PAR polymers, calpains	AIF	large-scale DNA fragmentation, mitochondrial permeability
Pyroptosis	intracellular PRRs	inflammasome	CASP-1, CASP-4/-5/-11	gasdermins	chromatin condensation, cellular swelling, PM permeabilization

Common inducers, key molecular and mechanistic hallmarks, and characterizations of distinct phenotypes of each RCD pathway. For more detailed definitions of these pathways, see Box 1. Abbreviations: AIF, apoptosis-inducing factor; BCL-2, B cell lymphoma 2; CASP, caspase; DAMP, damage-associated molecular patterns; DISC, death-inducing signaling complex; DR, death receptor; GPX4, glutathione peroxidase 4; GSH, glutathione; ICD, immunogenic cell death; IMM, inner mitochondrial membrane; LAP, LC3-associated phagocytosis; LOX, lipid oxidase; MLKL, mixed lineage kinase domain-like protein; MOMP, mitochondrial outer membrane permeabilization; MPO, myeloperoxidase; MPT, mitochondrial transition pore; NET, neutrophil extracellular traps; OMM, outer mitochondrial membrane; PARP1, poly(ADP-ribose) polymerase 1; PM, plasma membrane; PRR, pattern recognition receptors; PTP, permeability transition pore; PUFA, poly-unsaturated fatty acid; RIP, receptor interacting protein; ROS, reactive oxygen species; TLR, Toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β.