Fig. 3

Mechanism of necroptosis and its relationship with MAFLD. (1) TNF activates TNFR1 and recruits TRADD, TRAF2/5, clAP1/2 and LUBAC to form complex I. RIPK1, TAB2/3, Clap1/2 and LUBAC undergo M1 and K48 ubiquitination events and connect and recruit NEMO. IKKa, IKKb and RIPK ubiquitination events lead to the formation of the TAK complex, which phosphorylates IKK2 and activates the NF-KB pathway, cFLIP protein formation, K48 phosphorylation events and proteasome degradation. (2) CYLD or A20 deubiquitinates RIPK1 and induces dissociation of TRADD and RIPK1 to form complex IIa, including FADD, pro-caspase 8, and TRADD. Complex IIb includes RIPK1/3, FADD, and caspase 8. cFLIP inhibits complex IIa and IIb-induced apoptosis. (3) When caspase 8 is inhibited, complex IIc (the necrosome) is formed, containing RIPK1, RIPK3 and MLKL. RIPK1 phosphorylates RIPK3 and activates MLKL to cause changes in cell membrane permeability and necroptosis. The released substances cause inflammation. Activated TLR4 and ROS-activated RIPK3 may be related to liver fibrosis and insulin resistance. Inhibition of RIPK1 and MLKL may improve liver steatosis and insulin resistance