Skip to main content
. 2022 Jul 22;13(7):637. doi: 10.1038/s41419-022-05066-3

Fig. 1. Molecular pathways of three kinds of regulated necrosis (Necroptosis, Pyroptosis, and Ferroptosis).

Fig. 1

A MLKL stimulation by RIPK3 is necessary for the execution of necroptosis. The initiators of necroptosis include death receptors (FAS and TNF), TLRs, viruses, bacteria, others (e.g., STING, RIG-1), and they activate RIPK1, TICAM1, DAI/ZBP1, or others downstream factors, leading to the RIPK3/MLKL activation, membrane rupture, and necroptosis. DAMP (e.g., HMGB1, IL-1α, ATP…) can be released during this process. B Cleavage of GSDMD mediated by active caspase-1 or caspase-11 (mouse) or caspase-4, 5 (human) is the executor for pyroptosis. Proinflammatory cytokines IL-1β and IL-18 were cleaved by active caspase-1. Caspase-1 or caspase-4, 5, 11 can be induced by upstream initiators, DAMPS, PAMPs, LPS, and others, leading to GSDMD cleavage, membrane rupture, and finally pyroptosis. C Ferroptosis, an iron-dependent regulated necrosis, is generally induced by lipid peroxidation. Ferroptosis can be triggered by extrinsic pathway (e.g., GPX4, NOS, ALOX) or intrinsic pathway (e.g., inhibition system XC-, prevention cystine import). The membrane is damaged, followed by DAMP release. TLRs Toll-like receptors, RIPK3 receptor-interacting protein kinase 3, MLKL mixed lineage kinase domain-like, DAI IFN-regulatory factors, also known as ZBP1, GSDMD gasdermin D, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns.