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. 2023 Sep 18;19(15):4989–5003. doi: 10.7150/ijbs.88461

Figure 2.

Figure 2

Brief description of the PCD process. (A) Apoptosis: The pathways of apoptosis can be divided into intrinsic and extrinsic pathways. These two pathways are regulated by BAD/BCL-2 and signaling through membrane receptors (for example Death Receptors/TNFR/TLR), respectively, and then intersect at Caspase 3/7, leading to apoptosis. (B) Autophagy: The ULK1/2 complex is activated to phosphorylate multiple downstream factors, induces the formation of the phagosome, and further envelopes cargo to form the autophagosome. Autophagosome binds to the lysosome, the internal cargos are degraded by hydrolytic enzymes within the lysosome, and nutrients enter recirculation. (C) Pyroptosis: DAMPs/PAMPs stimulate intracellular receptors to form Inflammasome, which then activates Caspase-1. Activated Caspase-1 can cleave Pro-IL-1β, Pro-IL-18, and GSDMD to form active forms, and activated GSDMD-N forms oligomers to form pores in the membrane. IL-1β, IL-18, and HGMB-1 can be released from the pores, leading to pyroptosis. (D) Necroptosis: Activation of TNFR and other receptors induces the formation of the cIAP-TRADD-RIPKI-TRAF complex. Upon detection of the death signal, CYLD deubiquitinates RIPKI and induces the formation of the Caspase-8/10-TRADD-RIPKI-TRAF complex. Caspase-8/10 can be activated to induce apoptosis. When Caspase-8/10 is inhibited, the complex can trigger a downstream phosphorylation cascade reaction that leads to necroptosis. (E) Ferroptosis: Iron accumulation and ROS production from multiple metabolic pathways can lead to intracellular lipid peroxidation, which in turn triggers ferroptosis. System Xc- can inhibit ferroptosis by increasing the transport of cystine. (F) Cuproptosis: Copper ion carriers, such as Elsclomol, transport copper into the cells. Copper can bind to lipoylated mitochondrial enzymes in the TCA cycle then lead to their aggregation, and can also lead to destabilization of Fe-S clusters, which in turn leads to cell death. PCD, Programmed Cell Death; DAMPs, Damage-Associated Molecular Patterns; PAMPs, Pathogen-Associated Molecular Patterns; ROS, Reactive Oxygen Species.