FIGURE 1.

The pathophysiology of apoptosis and necroptosis. The apoptotic pathway can be executed by death receptor pathway, mitochondrial pathway, and endoplasmic reticulum pathway. The death receptors located on cellular membrane can be recognized and activated by death ligands, such as FasL and TNFα, which then is able to recruit associated adaptor proteins and assemble the death-inducing signaling complex. This complex leads to the activation of caspase-8, which can activate caspase-3/7 and caspase-6 sequentially, ultimately causing apoptosis. Intrinsic stimulations like oxidative stress cleaves BID to tBid, which can translocate to the mitochondria where it induces MOMP formation and CytC and AIF release. The released CytC activates caspase-9 and caspase-3/7 sequentially, ultimately leading to apoptosis. Moreover, in hepatocytes, caspase-8 and caspase-6 also participate in the cleavage of tBid and the release of CytC, thus strikingly amplifying the death signal initiated by death receptors. ERS also plays a critical role in apoptosis execution. On the one hand, ERS initiates the mitochondrial apoptosis reaction chain by downregulating Bcl-2 via IRE1α-JNK and PERK-eIFα-CHOP axis. On the other hand, ERS activates caspase-12, caspase-9, and caspase-3 sequentially, culminating in apoptosis. When capase-8 is inhibited, the death-inducing signaling complex mentioned above activates RIPK1, which then recruits RIPK3 and phosphorylates MLKL. The phosphorylated MLKL is then translocated to cellular membrane where it undergoes oligomerization and triggers necroptosis. Abbreviations: TNF, tumor necrosis factor; MOMP, mitochondrial outer membrane pore formation; BID, BH3-interacting domain death agonist; CytC, Cytochrome c; ERS, endoplasmic reticulum stress; RIPK1, receptor-interacting protein kinase-1; MLKL, pseudokinase mixed lineage domain-like.