Emestrin-Type Epidithiodiketopiperazines Inhibited Gasdermin D-Mediated Pyroptosis via Caspase-3/7 Activation.

ABSTRACT: Sepsis, a life-threatening dysregulated host response to infection, is frequently exacerbated by pyroptosis-a programmed, proinflammatory cell death process mediated by Gasdermin D (GSDMD) activation. Using high-throughput screening, we identified emestrin-type epidithiodiketopiperazines (ETPs) as potent inhibitors of GSDMD cleavage during pyroptosis in Tohoku Hospital Pediatrics-1 (THP-1, a human acute monocytic Leukemia cell line)-derived macrophages. Combined surface plasmon resonance and western blotting analyses demonstrated that these ETPs activate caspase-3/7, which in turn cleaves GSDMD at aspartic acid residue 87 to generate a p10 fragment. This process prevents the formation of the pore-forming p30 fragment, thereby mitigating its associated inflammatory effects. Building on thes

SUBMITTER: Geng B 

PROVIDER: S-EPMC12796841 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature