Emestrin-Type Epidithiodiketopiperazines Inhibited Gasdermin D-Mediated Pyroptosis via Caspase-3/7 Activation.
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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 these results, in vivo studies showed that a low dose of the lead emestrin-type ETP (compound 2) protected against lethal lipopolysaccharide (LPS)-induced septic shock and attenuated lung inflammation. This protective effect was further validated in the clinically relevant cecal ligation and puncture (CLP) model, where compound 2 significantly enhanced survival by suppressing the infiltration of GSDMD-positive neutrophils and monocytes. scRNA-seq of murine lung tissue showed that compound 2 suppressed LPS-induced systemic inflammation by inhibiting moDC maturation. Collectively, these findings establish the therapeutic potential of targeting GSDMD-driven pyroptosis with ETPs in sepsis and suggest their promise for clinical translation.