GL‐V9 inhibits Caspase‐11 activation‐induced pyroptosis by suppressing ALOX12‐mediated lipid peroxidation to alleviate sepsis

Background and Purpose Sepsis, caused by pathogen infection, poses a serious threat to human life. While the link between sepsis and pyroptosis via Caspase‐11 non‐canonical inflammasome activation is known, effective treatments remain lacking. Previous studies have confirmed that GL‐V9 has antifibrotic and antitumor activities, but whether it has a therapeutic effect on sepsis is unclear. The aim of this study was to investigate the anti‐inflammatory activity of GL‐V9 and its possible mechanism. Experimental Approach The caecal ligation and puncture (CLP) model was used to assess the antiseptic effects of GL‐V9 in vivo. Mouse bone marrow derived macrophages (BMDMs) and murine macrophages line J774A.1 also served as an in vitro Caspase‐11 activation induced pyroptosis model. Cellular functions and molecular mechanism were analysed using cell viability assay, PI uptake assay, western blotting, immunofluorescence and co‐immunoprecipitation. Key Results GL‐V9 reduced tissue damage and mortality in mice with sepsis, and decreased the secretion of inflammatory factors in vivo. In vitro , GL‐V9 suppressed Caspase‐11‐induced pyroptosis and prevented the release of LPS from early endosomes. Mechanistic studies revealed that GL‐V9 limits Caspase‐11 activation by inhibiting ALOX12‐mediated lipid peroxidation. Further studies confirmed that GL‐V9 did not further alleviate the symptoms and inflammatory response of septic mice in Alox12 deficient mice. Conclusion and Implications GL‐V9 exerts a powerful anti‐sepsis effect in vivo, which is associated with the inhibition of Caspase‐11 activation. Mechanistically, GL‐V9 may block LPS release from early endosomes by inhibiting ALOX12‐mediated lipid peroxidation. This suggests that GL‐V9 is a potential candidate for the treatment of sepsis.