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.