The gasdermin family of proteins are terminal effectors of pyroptosis.

Necrosulfonamide, disulfiram, and dimethyl fumarate are three inhibitors of gasdermin.

These inhibitors have complex mechanisms but uncharacterized off-target effects.

Disease-specific Gasdermin D mutations or polymorphisms remain undetermined.

Timing, redundancy, and non-lytic roles of gasdermin D should inform further studies.

The gasdermin family of proteins are central effectors of the inflammatory, lytic cell death modality known as pyroptosis. Characterized in 2015, the most well-studied member gasdermin D can be proteolyzed, typically by caspases, to generate an active pore-forming N-terminal domain. At least well-studied three pharmacological inhibitors (necrosulfonamide, disulfiram, dimethyl fumarate) since 2018 have been shown to affect gasdermin D activity either through modulation of processing or interference with pore formation. A multitude of murine in vivo studies have since followed. Here, we discuss the current state of research surrounding these three inhibitors, caveats to their use, and a set of guiding principles that researchers should consider when pursuing further studies of gasdermin D inhibition.

GSDMD

Gasdermin D

Necrosulfonamide

Disulfiram

Dimethyl fumarate

Succination

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