Table 1.

A comparison of features associated with various forms of apoptotic and non-apoptotic cell death

Cell death process	Death stimulus	Initiator	Mediator	Executioner	Hallmarks	Inhibitors
Apoptosis
Extrinsic Pathway	• Death ligand binding to receptors of the tumor necrosis factor (TNF) superfamily (e.g. FasL/FasR, TNFα/TNFR1, Apo3L/DR3, Apo2L/DR4, Apo2L/DR5)	Activation of TNF death receptors Recruitment of cytoplasmic adaptor proteins (e.g. FADD and TRADD)	Formation of death-inducing signaling complex (DISC), consists of FADD and procaspase-8	Caspase 3 and endonuclease activation	Caspase activation Cytochrome c release Plasma membrane blebbing Nuclear fragmentation Chromatin condensation and margination Externalization of phosphatidylserine on the plasma membrane	Caspase inhibitors
Intrinsic Pathway	• DNA damage • Growth factor withdrawal • Hypoxia • Viral infection • Toxins • Hyperthermia	Loss of mitochondrial transmembrane potential Mitochondrial outer membrane permeabilization (MOMP) Release of pro-apoptotic proteins into cytosol (e.g. cytochrome c)	Formation of apoptosome, consist of cytochrome c, Apaf-1 and procaspases-9 Caspase 9 activation
Necroptosis	• Death ligand (e.g. Fas, TNFα, TRAIL) binding to TNF receptor in caspase-inhibited cells	TNFR1 activation Recruitment of TRADD and RIPK1	In the absence of caspase 8, formation of the necrosome by phosphorylation of RIPK1 and RIPK3	Phosphorylation and oligomerization of MLKL proteins that insert into and permeabilize the plasma membrane	Plasma membrane permeabilization Swelling of organelles (e.g. mitochondria)	Necrostatins (e.g. Nec-1) Necrosulfonamide
Ferroptosis	• Inhibition of cystine import (e.g. erastin, SAS, glutamate) • Glutathione depletion (e.g. BSO) • GPX4 inactivation (e.g. RSL3) • AA depletion in presence of serum and glucose	System $x_{\text{c}}^{-}$ inhibition Inhibition of GCL Inhibition of GPX4	Unknown (possibly not needed)	Unchecked lipid peroxidation and oxidative lipid fragmentation; normally opposed by GPX4	Lipid peroxidation Iron-dependence	Lipophilic antioxidants (e.g. Fer-1, vitamin E) Iron chelators (e.g. DFO, CPX)
Oxidative glutamate toxicity	• High concentrations of extracellular glutamate	Inhibition of system $x_{\text{c}}^{-}$ result in glutathione depletion	Mitochondrial ROS production Opening of cyclic GMP-gated Ca2+ channels on plasma membrane	Ca2+-dependent activation of calpains triggering lysosomal membrane permeabilization, processing of BID and release of AIF1	Mitochondrial ROS production Ca2+ influx Oxidative stress	Antioxidants (e.g. vitamin E, idebenone) PD150606, a calpain inhibitor
Autophagic cell death	• In Bax/Bak double knockout MEFs or cells overexpressing antiapoptotic Bcl-2 or Bcl-xL proteins, treatment with etoposide, staurosporine, thapsigargin	Upregulation of Atg5 and Atg6	Unknown	Autophagosome and autolysosome formation	Large-scale sequestration of cytoplasmic contents in autophagosome and autolysosomes	Autophagy inhibitors (e.g. 3-MA, wortmannin)
Parthanatos	• UV • Alkylating agents (e.g. MNNG) • Ca2+ influx • ROS	Hyperactivation of Poly(ADP-ribose) polymerase 1 (PARP1)	Release of apoptosis-inducing factor (AIF) into the cytoplasm	Unknown mechanism that activates endonuclease	NAD+ and ATP depletion	PARP1 inhibitors

GSH reduced glutathione, GCL glutamate-cysteine ligase, GPX4 glutathione peroxidase 4, AA amino acid, FADD Fas-associated protein with death domain, TRADD tumor necrosis factor receptor type 1-associated DEATH domain protein