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Z-YVAD-FMK is a cell-permeable, irreversible peptide-based inhibitor specifically targeting Caspase-1 (interleukin-1β converting enzyme, ICE). The molecule consists of a benzyloxycarbonyl (Z) N-terminal capping group, the tetrapeptide sequence Tyr-Val-Ala-Asp (YVAD) which mimics the natural cleavage site of pro-IL-1β, and a C-terminal fluoromethyl ketone (FMK) warhead. The FMK group facilitates covalent binding to the active site cysteine of Caspase-1, effectively blocking its proteolytic activity. Z-YVAD-FMK is extensively utilized as a pharmacological probe in preclinical research to study the NLRP3/Caspase-1/GSDMD pathway, canonical inflammasome signaling, and the induction of pyroptosis. It has shown efficacy in experimental models of inflammatory diseases, myocardial fibrosis, diabetic nephropathy, and cerebral ischemia by reducing the maturation and release of proinflammatory cytokines such as IL-1β and IL-18.
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