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

作者：Li Chen, Dongsheng Bai, Jiaying Du, Jiawei Zhao, Chen Zhou, Chunyang Gu, Yuxiang Wang, Lulu Zhang, Na Lu, Yue Zhao · 发表于：British Journal of Pharmacology · 年份：2025 · DOI：10.1111/bph.70053 · 被引用次数：3 · 研究领域：Inflammasome and immune disorders、Immune Response and Inflammation、Cholesterol and Lipid Metabolism

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 ...