Fig. 7.

The core molecular mechanisms of necroptosis. FASL, TRAIL, TNF and IFN-1 activate each of their receptors, and MLKL, RIPK1 and RIPK3 are recruited to assemble the necrosome through phosphorylation. Phosphorylation-mediated activation of MLKL and subsequent MLKL-mediated membrane pore formation result in necroptosis. In response to TNF-α-induced necroptosis, PGAM5 is recruited to the RIPK1/RIPK3 complex on the outer mitochondrial membrane, where it triggers Drp1-mediated mitochondrial fragmentation and the release of large amounts of ROS, thereby activating PARP-1 and resulting in a decrease in NAD⁺ production and subsequent cycling, which is considered an obligatory step in necroptosis. Abbreviations: FASL, factor-related apoptosis ligand; TRAIL, TNF-related apoptosis-inducing ligand; TNF, tumor necrosis factor; IFN-1, interferon-1; MLKL, mixed lineage kinase domain-like protein; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; PGAM5, phosphoglycerate mutase family 5; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 related factor 2; PARP-Q, poly-ADP-ribose polymerase; NAD⁺, nicotinamide adenine dinucleotide