CASP4 (caspase-4) is an inflammatory caspase that serves as a cytosolic pattern recognition receptor for lipopolysaccharide (LPS) from Gram-negative bacteria 1. The protein directly binds LPS through its CARD domain with high specificity and affinity, inducing oligomerization and autoprocessing to generate an active p10 form 12. Once activated, CASP4 cleaves gasdermin D (GSDMD) to trigger pyroptosis, a form of inflammatory cell death characterized by membrane pore formation and cytokine release 34. CASP4 can also directly process pro-IL-18 with efficiency similar to caspase-1, enabling IL-18 release independently of canonical inflammasomes 5. The enzyme plays critical roles in host defense against bacterial infections and inflammatory diseases. In blood-brain barrier endothelial cells, CASP4 activation leads to barrier breakdown during sepsis 6. However, some pathogens like Shigella flexneri evade CASP4-mediated immunity through ADP-riboxanation modifications that block caspase autoprocessing and GSDMD cleavage 7. Therapeutically, CASP4-mediated pyroptosis can be inhibited by disulfiram, which blocks GSDMD pore formation 4.