FIGURE 1.

A brief overview of the main molecular mechanisms in PCDs (A) Apoptosis is initiated by the intrinsic and extrinsic pathways. In the intrinsic pathway, DNA damage activates p53, and subsequently activates Puma/Noxa to induces signaling genes including proapoptotic proteins (Bax, Bak, tBid), apoptosome (Cyt c, Apaf-1, pro-Caspase-9), antiapoptotic protein (Bcl-2), and apoptosis execution factors (caspase-3/7). The extrinsic pathway of apoptosis is initiated by the binding of TNF to its receptors, leading to the recruitment of FADD and caspase-8. In addition, caspase-8 can cleave Bid to t-Bid, which participates in the intrinsic pathway of apoptosis (B) Autophagy is initiated by nutrient sensoring, including AMPK, PI3K-1, mTORC1. Autophagosome formation and maturation are mediated PI3K-III complex, ATG3, and LC3. Finally, the autophagosome contents undergo is degraded by lysosomes (C) Necroptosis is initiated by the binding of TNF-α and the receptor TNFR. Under conditions of caspase-8 (initiator caspase of extrinsic apoptosis) is not active, the formation of necroptosome (integration of phosphorylated RIPK1 and RIPK3) induces the MLKL phosphorylation and oligomerization. Finally, the MLKL oligomers translocation to membranes and disrupt it to kill cells (D) Pyroptosis is triggered by various pathogens and danger signals. These signals activate NLRP3 inflammasome, which consists of NLRP3, ASC and procaspase-1, and subsequently leads to cleavage of GSDMD and pro-IL-1β and pro-IL-18. Finally, the N-terminal fragment of GSDMD targets to membrane to form membrane pores and induces inflammatory cell death (E) Ferroptosis is triggered by severe lipid peroxidation with ROS and iron overload, leading to membrane damage. The uptake of Fe²⁺ is regulated by DMT1. The lipid peroxidation is mainly caused by loss of activity of GSH and GPX4. The xCT also functions in regulating ferroptosis via Cys. In addition, p53, an initiator of intrinsic apoptosis, controls ferroptosis by regulation of the production of GSH. Abbreviations: Cyt c, cytochrome c; Apaf-1, apoptotic peptidase activating factor 1; Bcl-2, B cell chronic lymphocytic leukaemia/lymphoma-2; FADD, Fas-associated death domain; AMPK, AMP activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; PI3K-1, phosphatidylinositol 3 kinase-1; ATG3, autophagy-related gene 3; LC3, light chain 3; TNF, tumor necrosis factor; TNFR, TNF receptor; TRAF2, TNF receptor associated factor 2; TRADD, TNFR1-associated death domain protein; cIAP1/2, cell inhibitor of apoptosis protein-1/2; RIPK1/3, receptor interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like protein; NLRP3, nod-like receptor protein-3; ASC, apoptosis-associated speck-like protein; GSDMD, gasdermin D; IL, interleukin; ROS, reactive oxygen species; DMT1, divalent metal ion transporter 1; xCT, cystine/glutamate antiporter SLC7A11; Cys, cystine; GSH, glutathione; GPX4, glutathione peroxidase 4.