YL-109 attenuates sepsis-associated multiple organ injury through inhibiting the ERK/AP-1 axis and pyroptosis by upregulating CHIP

作者：Miao Wang, Jia Liao, Lin Wan, Lucen Jiang, Kangli Peng, Xingyu Su, Hang Li, Huadong Wang, Yiyang Wang · 发表于：Biomedicine & Pharmacotherapy · 年份：2024 · DOI：10.1016/j.biopha.2024.116633 · 被引用次数：15 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Cell death mechanisms and regulation

Sepsis is a severe inflammatory disorder that can lead to life-threatening multiple organ injury. Lipopolysaccharide (LPS)-induced inflammation is the leading cause of multiple organ failure in sepsis. This study aimed to explore the effect of a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), on LPS-induced multiple organ injury and the molecular mechanisms underlying these processes. The results showed that YL-109 protected against LPS-induced high mortality, cardiac dysfunction, pulmonary and intestinal injury through inhibiting the proinflammatory response, NLRP3 expression and pyroptosis-associated indicators in mouse tissues. YL-109 suppressed LPS-initiated cytokine release, pyroptosis and pyroptosis-related protein expression in HL-1, IEC-6 and MLE-12 cells, which was consistent with the results of the in vivo experiments. Mechanistically, YL-109 reduces phosphorylated ERK (extracellular signal-regulated kinase) levels and NF-κB activation, which are achieved through upregulating CHIP (carboxy terminus of Hsc70-interacting protein) expression, thereby inhibiting c-Jun and c-Fos activation as well as NLRP3 expression. As an E3 ligase, CHIP overexpression obviously promoted the degradation of phosphorylated ERK and inhibited the expression of NF-κB-mediated NLRP3 in cells stimulated with LPS. The protective effects of YL-109 against cardiac, pulmonary and intestinal damage, inflammation and pyroptosis caused by LPS were eliminated in CHIP knockout mice....