TABLE 1.

Pyroptosis inhibitors in eye disease.

Inhibitor	Structure	Mechanism	Animal models of eye disease	References
NLRP3 Inhibitors
MCC950		Specifically, it inhibits canonical and non-canonical NLRP3 inflammasome activation in vitro. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain	Ocular hypertension	Zhang et al. (2019b), Sui et al. (2020), Wooff et al. (2020)
			Oxygen-induced ischemic retinopathy
			Photo-oxidative damage-induced retinal degeneration
INF39		NACHT ATPase inhibitor. Reduces NLRP3, IL-1β, and caspase-1 expressions and attenuates the pyroptosis level	-	Huang et al. (2020)
Tranilase		Binds NACHT domain and inhibits the NLRP3–NLRP3 interaction and the expression of cytokines and chemokines	-	Liu et al. (2016b), Yumnamcha et al. (2019)
β-Carotene		Protects the eye from oxidative stress, apoptosis, mitochondrial dysfunction, and inflammation	-	Camelo et al. (2020), Johra et al. (2020)
Caspase-1 Inhibitor
VX-765		Decreases caspase-1 and inhibits the mature IL-1β and IL-18 and caspase-1–mediated pyroptosis	-	Lin et al. (2018), Li et al. (2021)
GSDMD Inhibitors
Necrosulfonamide		Inhibits the expression of NLRP3 and GSDMD and reverses the effects of high glucose on ARPE-19 cell proliferation	-	Xi et al. (2020)
Disulfiram		Blocks GSDMD pore formation, reduces the proportion of pyroptotic cells, and prevents cells against hyperosmotic stress–induced cytotoxicity	Diabetic retinopathy (OLETF rats)	Ito et al. (2010), Kanai et al. (2010), Kanai et al. (2012), Deguchi et al. (2020), Zhang et al. (2021)
			Ocular hypertension induced by rapid infusion of 5% glucose solution
			Endotoxin-induced uveitis
Other Indirect Inhibitors of the Inflammasome
Glyburide		Inhibition of NLRP3 inflammasome activation and release of IL-1β by changing ion channel activity	Alu RNA–mediated geographic atrophy	Kerur et al. (2013), Gan et al. (2020a)
Ticagrelor		Induces degradation of Cl− channel to block chloride outflow and inhibits the interaction of NLRP3 with ASC to inhibit activation of the NLRP3 inflammasome	ABCA4−/− mouse model of retinal degeneration	Lu et al. (2018), Lu et al. (2019), Huang et al. (2021)
TAK-242		TLR4 inhibitor, which decreases the expression levels of TLR4 downstream signaling molecules (MyD88, NF-κB, TRAF6, NLRP3) and inflammatory factors (IL-1β and IL-18)	-	Hu et al. (2017)
N-Acetylserotonin		TLR4 inhibitor, which alleviates the expression of IL-1β in retinal ischemia–reperfusion rats via the TLR4/NF-κB/NLRP3 pathway	-	Liu et al. (2021)
A740003		P2X7R inhibitor, which inhibits the activation of NLRP3 inflammasome and phosphorylation of IKBα	Oxidized low-density lipoprotein model (retinal inflammation and neovascularization)	Yang et al. (2021)
A438079		P2X7R inhibitor, which inhibits P2X7R–NLRP3 pathway reduced NLRP3 inflammasome expression	Ocular hypertension	Sakamoto et al. (2015), Zhang et al. (2019b)
			N-Methyl-d-aspartic acid–induced retinal injury
TAS-116		HSP90 inhibitor, which prevents the activation of caspase-1, subsequently reducing the release of mature IL-1β	-	Ranta-Aho et al. (2021)
Xanthone		Inhibits cross-link ASC oligomerization, endogenous NLRP3 oligomerization, the cleavage of GSDMD, and the release of IL-1β	LPS-induced keratitis	Cui et al. (2021)
Verapamil		Inhibition of thioredoxin-interacting protein and inflammasome assembly	STZ-induced diabetic retinopathy	Eissa et al. (2021)
Calcitriol		Alleviates hyperosmotic stress–induced corneal epithelial cell damage through inhibiting the NLRP3–ASC–caspase-1–GSDMD pyroptosis pathway	Corneal wound in STZ-induced diabetic mice	Wang et al. (2021b), Zhang et al. (2021)
Butyrate		Decreased NLRP3, caspase-1, and IL-1β mRNA transcripts and NLRP3 protein expression	Corneal alkali burn	Bian et al. (2017)
Epigallocatechin-3-gallate		Inhibits the ROS/TXNIP/NLRP3 inflammasome axis to reduce ROS accumulation, NLRP3 inflammasome activation, Müller cell proliferation, and production of the pro-angiogenic factors	STZ-induced diabetic retinopathy	Du et al. (2020)

OLETF rats, Otsuka Long Evans Tokushima Fatty rats; LPS, lipopolysaccharide; STZ, streptozotocin.