Chemical Modulation of Gasdermin-Mediated Pyroptosis and Therapeutic Potential

• Gasdermins are critical effectors of inflammatory mediator release and pyroptosis . • Gasdermins sit as a bottleneck between diverse upstream stimuli and effector release. • This central position makes gasdermins prime targets for a variety of human diseases. • Here we discuss the known function and regulation of gasdermins in human disease. • We also describe strategies to target gasdermin-mediated pyroptosis therapeutically. Pyroptosis, a lytic form of programmed cell death, both stimulates effective immune responses and causes tissue damage. Gasdermin (GSDM) proteins are a family of pore-forming executors of pyroptosis. While the most-studied member, GSDMD, exerts critical functions in inflammasome biology, emerging evidence demonstrates potential broad relevance for GSDM-mediated pyroptosis across diverse pathologies. In this review, we describe GSDM biology, outline conditions where inflammasomes and GSDM-mediated pyroptosis represent rational therapeutic targets, and delineate strategies to manipulate these central immunologic processes for the treatment of human disease.