2. Academic Validation
  3. Glucocorticoid reduces mortality in LPS-induced sepsis mouse model by inhibiting JAK1/STAT3-mediated inflammatory response and restoring tricarboxylic acid cycle

Glucocorticoid reduces mortality in LPS-induced sepsis mouse model by inhibiting JAK1/STAT3-mediated inflammatory response and restoring tricarboxylic acid cycle

  • Life Sci. 2025 Aug 15:375:123744. doi: 10.1016/j.lfs.2025.123744.
Yudan He 1,  Xinyue Chen 2,  Jiayue Zhong 2,  Canfeng Lin 2,  Jieying Situ 2,  Bing Liu 2,  Yiwen Yan 2,  Shuiqing Gui 3,  Chengzhou Mao 4,  Shaojun Xing 5
Affiliations

Affiliations

  • 1 Intensive Care Unit, The First Affiliated Hospital of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 2 Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 3 Intensive Care Unit, The First Affiliated Hospital of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 4 Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: maocz@szu.edu.cn.
  • 5 Intensive Care Unit, The First Affiliated Hospital of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; Marshall Laboratory of Biomedical Engineering, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China. Electronic address: shaojun-xing@szu.edu.cn.
PMID: 40408938 DOI: 10.1016/j.lfs.2025.123744
Abstract

Aims: Sepsis is characterized by a systemic inflammation disorder and multi-organ dysfunction caused by Infection. Glucocorticoids (GCs), as anti-inflammatory properties drugs, are widely used for the management of patients with inflammatory diseases, including sepsis. However, the therapeutic effect and underlying mechanisms of GCs on sepsis remain incompletely understood.

Materials and methods: Mouse sepsis models were constructed using intraperitoneal injection of lipopolysaccharide (LPS) and treated with synthetic GC dexamethasone (DEX). Systemic inflammation and organ injury were evaluated by histological staining, immunophenotypic analysis, and detection of inflammatory cytokines. Inflammatory signaling pathways were identified by western blot (WB) and RT-qPCR. Finally, targeted metabolomics were conducted to examine metabolic changes.

Key findings: Subcutaneous administration of DEX significantly alleviate LPS-induced acute organ injury and systemic inflammation, thereby reducing mortality in septic mice. DEX substantially reduced the amounts of intrahepatic neutrophils/macrophages, and inflammatory cytokines expressions in the livers of septic mice and in LPS-stimulated bone-marrow-derived macrophages (BMDMs). Mechanistically, DEX inhibit JAK1/STAT3 signaling pathway both in livers and BMDMs. Pharmacological inhibition of JAK1 or STAT3 via Upadacitinib or Stattic, respectively, partially mimic the anti-inflammatory function of GC, including the reduction of intrahepatic macrophages, proinflammatory cytokines production, and mortality in septic mice. Additionally, DEX could also promote the rewiring of tricarboxylic acid (TCA) cycle in the livers of septic mice.

Significance: This study provides important insights into the molecular and metabolic mechanisms underlying GCs-mediated anti-inflammatory reactions.

Keywords

Glucocorticoids; Immunometabolism; JAK1/STAT3; Liver injury; sepsis.

Figures
Products