Gasdermin D and Gasdermin E (GSDMD/GSDME)

Gasdermin D (GSDMD) and Gasdermin E (GSDME) are the primary executioner proteins of pyroptosis, a highly inflammatory form of programmed cell death. GSDMD is typically activated by inflammatory caspases (Caspase-1, -4, -5, and -11) following the detection of pathogens or cellular stress by inflammasomes (UniProt P57764). Upon cleavage, the N-terminal fragment of GSDMD translocates to the plasma membrane, where it oligomerizes to form large pores that facilitate the release of pro-inflammatory cytokines like IL-1β and IL-18, eventually leading to osmotic cell lysis. GSDME, originally identified as a deafness-associated gene (DFNA5), is activated by Caspase-3, which can switch a cell's fate from non-inflammatory apoptosis to inflammatory pyroptosis, particularly in response to chemotherapy (Wang et al., Nature 2017; UniProt O60437). In therapeutic development, GSDMD is a major target for treating hyper-inflammatory conditions such as sepsis, cytokine release syndrome, and various autoimmune disorders where excessive pyroptosis drives tissue damage. Conversely, GSDME is frequently explored in oncology; its expression is often silenced in tumors to evade immune detection, and its reactivation or modulation is investigated as a means to enhance the immunogenicity of cancer cell death. Current pharmacological efforts focus on small-molecule inhibitors that prevent gasdermin pore assembly or covalent modifiers that block the cleavage sites, offering a novel approach to controlling inflammation and enhancing anti-tumor immunity.

Other names

DFNA5 (GSDME)FIP2 (GSDMD)Gasdermin-DGasdermin-EGSDMD-NGSDME-N

Drugs targeting this pathway primarily act by inhibiting the oligomerization of the N-terminal gasdermin fragments or by preventing the proteolytic cleavage of the full-length pro-protein. For example, Disulfiram covalently modifies Cys191 in human GSDMD to block pore formation (Hu et al., Nature Immunology 2020). Dimethyl fumarate (DMF) succinylates GSDMD at critical cysteine residues, preventing its interaction with caspases and subsequent activation (Humphries et al., Science 2020). Other strategies include small-molecule inhibitors that bind the N-terminal domain to prevent membrane insertion or the use of caspase inhibitors to stop the upstream activation of the gasdermin proteins.