Table 2.
Treatment targets and mechanisms in the modes of cell death in COVID-19.
| Cell death mode | Potential therapeutic targets | Treatment pathways and mechanisms | Potential drugs | References |
|---|---|---|---|---|
| Necroptosis | RIPK1 | Inhibits RIPK1 specifically | Nec-1 | (23) |
| Blocks RIPK1 activation and further blocks the TNFα-induced necroptosis | Primidone | (70) | ||
| MLKL | Decreases the phosphorylation of MLKL | Necrosulfonamide (NSA) | (59) | |
| Inhibits pMLKL accumulation in the membrane to prevent the plasma membrane from disintegration | Nocodazole, Cytochalasin B, and Brefeldin A(NCB) | 71) | ||
| TNF-α and IFN-γ | Blocks TNF-α and IFN-γ to alleviate necroptosis in COVID-19 | Neutralizing antibody (Anti-TNF-α, Anti-IFN-γ) | (77) | |
| Anexelekto (AXL) | Oppresses the p38/mitogen-activated protein kinase (MAPK) pathway and further reduces cytokine production and virus replication | Gilteritinib | (89) | |
| NF-κB pathway | Inhibits NF-κB pathway and reduces ROS damage. | Nec-1 | (23) | |
| DAMPs and pro-inflammatory cytokines | Alleviates the release of DAMP and pro-inflammatory cytokines. | Nec-1 | (23) | |
| Pyroptosis | Release of cytokine | Inhibits the cytokine storm. Improves the survival rate of COVID-19. |
IL-1 inhibitor (Anakinra) half-life-prolonged IL-1β (canakinumab) rilonacept |
(25, 90, 91) |
| ROS | Alleviates inflammatory reaction by activating the antioxidant system. | Rapamycin, genipin, agrabine, and resveratrol | (24) | |
| ASC oligomerization | Blocks ASC oligomerization. Inhibits K+ efflux and caspase-1 activation. |
B-hydroxybutyrate (BHB) | (92) | |
| NLRP3 oligomerization | Binds to the NACHT domain of NLRP3 to inhibit its oligomerization. | Tranilast | (24) | |
| Inhibits the expression level of NLRP3 inflammasome-related proteins. | Rapamycin, genipin, agrabine, and resveratrol | (93) | ||
| Autophagy | Induces autophagy. Inhibits macrophage mitochondrial damage. |
Resveratrol, HU-433 and HU-308. | (94, 95) | |
| Ferroptosis | System Xc- | Inhibits system Xc- to cause intracellular glutathione (GSH) depletion, inducing ferroptosis. | Erastian, Sulfasalazine (SAS), Sorafenib, extracellular glutamate accumulation. |
(96) |
| ROS regulation | Inhibits lipid oxidation and decreases ROS of intracellular lipids. | Lipid antioxidants (vitamin E, Fer-1, and Lip-1). | (97, 98) | |
| Prevents the formation and scavenging of ROS. | Reducing agents (methemoglobin reductase, ascorbic acid, and glutathione). | (99) | ||
| Iron | Binds to free iron to inhibit its redox properties. Prevents membrane lipid oxidation and the Fenton reaction. Removes iron from iron-binding proteins. |
Iron chelators (desferrioxamine, deferoxamine mesylate, and deferrione) | (25, 100, 101) | |
| Iron autophagy | Inhibits fermodulin. | Analogues of fermodulin-1 and liproxistatin-1. | (102) |
ASC, Apoptosis-associated speck-like protein containing a caspase recruitment domain; COVID-19, Coronavirus Disease 2019; DAMP, damage-associated molecular patterns; IFN-γ, interferon-γ; IL, interleukin; MLKL, mixed lineage kinase domain-like pseudokinase; NF-κB, Nuclear factor-κB; Nec-1, Necrostatin-1; NLRP3, NLR family, pyrin domain containing 3; RIPK1, receptor-interacting protein kinase 1; ROS, reactive oxygen species; TNF-α, Tumor Necrosis Factor-alpha.