Progress in small-molecule inhibitors of gasdermin D

As a key mediator of pyroptosis, Gasdermin D (GSDMD) drives pro-inflammatory cell death through caspase-mediated cleavage to form membrane pores, which is closely linked to the pathogenesis of sepsis, cancer, and autoimmune diseases. Recent advances in GSDMD inhibitor development primarily focus on key steps: blocking caspase-mediated cleavage, inhibiting N-terminal oligomerization, or disrupting pore formation. Examples include small-molecule drugs targeting Cys191/192 such as DMF, DSF, NSA, and NU6300, as well as molecules targeting other residues like mafenide, GI-Y1, and GI-Y2. The elucidation of high-resolution structures of caspase-GSDMD complexes and pore assembly mechanisms has facilitated the emergence of novel targeting strategies, providing a critical basis for rational design. Despite progress, challenges such as off-target effects and low clinical translation rates persist. Optimizing specificity and exploring disease-specific applications remain pivotal to advancing these inhibitors as therapeutic agents. Current research focuses on developing clinically translatable, highly effective, and safe GSDMD-targeted therapies through structure-guided optimization, drug repurposing, innovations in precision delivery systems, and synergistic mechanism approaches.