Extracellular caspase-1: a critical inducer and a therapeutic target of lung injury in gut ischemia-reperfusion

, hypoxia-reoxygenation promoted GSDMD-dependent eCasp-1 release, and pharmacological inhibition of GSDMD reduced this release, supporting a contributing role of GSDMD-mediated membrane permeabilization in eCasp-1 release. Gut I/R demonstrated robust GSDMD-dependent release of eCasp-1. Functionally, eCasp-1 engaged TLR4 on macrophages, eliciting robust inflammatory cytokine release and organ injury. Importantly, we developed a novel peptide, C16, designed to specifically inhibit the eCasp-1-TLR4 interaction. In gut I/R, C16 administration exerted therapeutic benefits, markedly reducing systemic inflammation, attenuating acute lung injury (ALI), and significantly improving the survival. Our findings identify eCasp-1 as a new alarmin, that contributes to ALI through TLR4 signaling, with GSDMD-dependent processes contributing to its extracellular release. Targeting eCasp-1 with C16 offers a promising therapeutic strategy against ALI in acute inflammation.