Guggulsterone protects against lipopolysaccharide-induced inflammation and lethal endotoxemia via heme oxygenase-1

Int Immunopharmacol. 2023 Nov;124(Pt B):111073. doi: 10.1016/j.intimp.2023.111073. Epub 2023 Oct 14.


Guggulsterone (GS) is a phytosterol used to treat inflammatory diseases. Although many studies have examined the anti-inflammatory activities of GS, the detailed mechanisms of GS in lipopolysaccharide (LPS)-induced inflammation and endotoxemia have not yet been examined. Therefore, we investigated the anti-inflammatory effects of GS on LPS-induced inflammation. In murine peritoneal macrophages, the anti-inflammatory activity of GS was primarily mediated by heme oxygenase-1 (HO-1) induction. HO-1 induction by GS was mediated by GSH depletion and reactive oxygen species (ROS) production. The ROS generated by GS caused the phosphorylation of GSK3β (ser9/21) and p38, leading to the translocation of nuclear factor erythroid-related factor 2 (Nrf2), which ultimately induced HO-1. In addition, GS pretreatment significantly inhibited inducible nitric oxide synthase (iNOS), iNOS-derived NO, and COX-2 protein and mRNA expression, and production of COX-derived prostaglandin PGE2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). In a mouse model of endotoxemia, GS treatment prolonged survival and inhibited the expression of inflammatory mediators, including IL-1β, IL-6, and TNF-α. GS treatment also inhibited LPS-induced liver injury. These results suggest that GS-induced HO-1 could exert anti-inflammatory effects via ROS-dependent GSK (ser21/9)-p38 phosphorylation and nuclear translocation of Nrf2.

Keywords: Endotoxemia; Guggulsterone; Heme Oxygenase-1 (HO-1); Lipopolysaccharide; Reactive Oxygen Species (ROS).

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Endotoxemia* / chemically induced
  • Endotoxemia* / drug therapy
  • Heme Oxygenase-1 / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides* / pharmacology
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Lipopolysaccharides
  • pregna-4,17-diene-3,16-dione
  • NF-kappa B
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Heme Oxygenase-1
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • Anti-Inflammatory Agents
  • Nitric Oxide Synthase Type II