Targeting Novel Regulated Cell Death: Pyroptosis, Necroptosis, and Ferroptosis in Diabetic Retinopathy

Figures

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  FIGURE 1. Overview of pyroptosis. Pyroptotic priming signals are usually triggered by endogenous cytokines and activate the NF-κB signaling pathway to induce the transcription of inactive NLRP3 and pro-IL-1β. Activation signals are triggered by the stimulation of DAMPs or PAMPs, stimulating NLRP3 oligomerization to recruit ASC and pro-caspase-1 and then form the NLRP3 inflammasome. Activated caspase-1 cleaves GSDMD to release the N-terminal domain and form the plasma membrane pore, leading to pyroptosis. Activated caspase-1 promotes the maturation and secretion of IL-1β. In addition, LPS binds to pro-caspase-4/5/11 to activate it, inducing pyroptosis via cleavage of GSDMD and formation of pores. Activated caspase-4/5/11 can also induce K+ efflux and activate the NLRP3 inflammasome. Abbreviations: ASC, apoptosis speck-like protein; DAMPs, damage-associated molecular patterns; GSDMD, gasdermin D; IKKα/β, IkB kinase α/β; IL-1β, interleukin-1β; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; TAK1, beta-activated kinase 1; TLR, toll-like receptor.

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  FIGURE 2. Overview of necroptosis. With stimulation of TNFα, TNFR1 recruits TRADD and binds with RIPK1, combining with TRAF2 and cIAP1/2 to form complex I. RIPK1 can be ubiquitinated by cIAP1/2, which promotes dissociation of TRADD and RIPK1 from complex I to trigger apoptosis or necroptosis. In apoptosis, FADD and caspase-8 are recruited to TRADD and RIPK1, respectively, to form complex IIa and complex IIb. Caspase-8 is activated, and apoptosis is induced. In necroptosis, when caspase-8 is inhibited, RIPK1 phosphorylates and activates RIPK3 to form necrosome complexes and phosphorylate MLKL. Phosphorylated MLKL undergoes oligomerization and migrates to the plasma membrane, where it induces necroptosis by initiating membrane rupture. Abbreviation: cIAP, cellular inhibitors of apoptosis protein; FADD, Fas-associated death domain; IKKα/β, IkB kinase α/β; MLKL, mixed lineage kinase domain-like protein; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor interacting protein kinase 3; TAK1, beta-activated kinase 1; ITLR, toll-like receptor; TRADD, TNF receptor-associated death domain; TRAF, TNF receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β;…

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  FIGURE 3. Overview of ferroptosis. The figure shows four systems regulating ferroptosis. Iron metabolism, Fe3+ is transferred into the cell through TFR1 and reduced to Fe2+ by STEAP3. Fe2+ is transported to the cytoplasm through DMT1. Excess Fe2+ causes the Fenton reaction and the initiation of lipid peroxidation, OH−. GSH-GPX4 pathway GSH synthetization is catalyzed by GSS and γ-GCS. GPX4 converts GSH to GSSG to inhibit lipid ROS production. Lipid metabolism and OH− promote the oxidation of PUFAs on the cell membrane, leading to the accumulation of PE-PUFA-OOH and 4-HNE generation. PE-PUFA-OOH can be repaired by GPX4 to reduce lipid hydrogen. In the mevalonate pathway, FSP1 is recruited to the cell membrane and decreases CoQ and suppresses lipid peroxidation, which mediates a nonmitochondrial CoQ antioxidant system. Abbreviations: ACSL4, acyl-CoA synthetase long-chain family member 4; CoQ, coenzyme Q; Cys, cysteine; DMT1, divalent metal transporter 1; FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSSG, oxidized glutathione; LPCAT3, lysophosphatidylcholine acyltransferase 3; NCOA4, nuclear receptor coactivator 4;…