Table 4.

GSDMD inhibitors

Inhibitor	IC50	Mechanisms of action	Off-target effects	GSDMD-related disease model
Necrosulfonamide (NSA)44,509–511	~10 μM	Binding directly to Cys191 of GSDMD and inhibiting the oligomerization of GSDMD-NT	Binding to Cys86 of MLKL and blocking necroptosis	LPS-induce sepsis, AD, AS, ALF
Disulfiram (DSF).45,52,383,384,514,516–519.	~10 μM	Modifying Cys191 of GSDMD and inhibiting the oligomerization of GSDMD-NT	Modifying Cys133 in the TLR-binding partner MD-2 and preventing LPS recognition; Inhibiting NLRP3 signaling	LPS/CLP-induced sepsis, ulcerative colitis, AS, obesity and metabolic dysfunction, SARS-CoV-2 infection, ARDS, DN, NAFLD
Dimethyl fumarate (DMF)46,409	<10 μM	Succinating Cys191 of GSDMD, blocking caspase-GSDMD interactions and inhibiting the oligomerization of GSDMD-NT	Succinating GSDME at Cys45; dopamine beta-hydroxylase; caspase-1; caspase-3	LPS-induced sepsis, FMF, EAE, HCC
Itaconate320,523,531–533	Not known	Binding to GSDMD via Cys77 and blocking caspase-GSDMD interactions	Inhibiting NLRP3 and caspase-1	ARDS, IBD, LPS-induced sepsis
C202-2729503	Not known	Binding directly to the GSDMD-NT and inhibiting the oligomerization of GSDMD-NT	Not known	EAE
Caffeic acid (CA)522	Not known	Binding directly to GSDMD and blocking GSDMD cleavage	Not known	LPS-induced sepsis
GSDMD inhibitor Y1 (GI-Y1)445	Not known	Binding to GSDMD via Arg7 and inhibiting the oligomerization of GSDMD-NT	Not known	Myocardial I/R injury

AD Alzheimer’s disease, AS atherosclerosis, ALF acute liver failure, ARDS acute respiratory distress syndrome, CLP cecum ligation and puncture, DN diabetic nephropathy, EAE experimental autoimmune encephalomyelitis, FMF familial Mediterranean fever, HCC hepatocellular carcinoma, IBD inflammatory bowel disease, I/R ischemia/reperfusion, LPS lipopolysaccharide