Novel GSDMD inhibitor GI-Y1 attenuates sepsis-induced myocardial dysfunction by targeting Gasdermin D and inhibiting Gasdermin D-mediated pyroptosis.

Sepsis-induced myocardial dysfunction is a life-threatening complication with significant implications for clinical outcomes in critically ill patients. Emerging evidence indicates that the pharmacological targeting of Gasdermin D (GSDMD)-mediated pyroptosis represents a novel therapeutic approach for septic myocardial dysfunction. The GSDMD inhibitor Y1 (GI-Y1), a new small-molecule inhibitor developed through structure-based virtual screening against the GSDMD-N terminal domain, demonstrates selective binding affinity and potent inhibitory activity as shown in preliminary screening assays. Our systematic evaluation revealed that GI-Y1 significantly improved cardiac function and reduced myocardial injury in septic mice induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). GI-Y1 effectively inhibited GSDMD-mediated pyroptosis both in vivo and in vitro. Importantly, genetic validation experiments conducted using GSDMD-knockout (Gsdmd) mice and siRNA-mediated knockdown of GSDMD in cardiomyocytes demonstrated a complete abrogation of GI-Y1's therapeutic effects, confirming that the cardioprotective efficacy of GI-Y1 against septic cardiac dysfunction relies on GSDMD. Notably, macrophage membrane-coated GI-Y1 nanoparticles (GI-Y1@MM-NPs) exhibited enhanced therapeutic efficacy in alleviating inflammation and cardiac dysfunction in septic mice when compared to free GI-Y1. Collectively, these findings indicate that GI-Y1 exerts protective effects on sepsis-related cardiac dysfunction by targeting GSDMD and inhibiting its mediated pyroptosis. GI-Y1 and GI-Y1@MM-NPs may serve as effective therapeutic strategies for treating sepsis-induced myocardial dysfunction.