Cordycepin improves liver fibrosis and the intestinal flora disturbance induced by 3,5-diethoxycarbonyl-1,4-dihydroxylidine in mice

Eur J Pharmacol. 2025 Jan 15:987:177172. doi: 10.1016/j.ejphar.2024.177172. Epub 2024 Dec 15.

Abstract

Background and aims: Studies have shown that improving the intestinal flora can alleviate the progression of liver fibrosis. Cordycepin has shown potential anti-inflammatory and anti-fibrosis effects. In this study, we aimed to investigate the effects of cordycepin on liver fibrosis and how it affects the intestinal flora composition to determine a potentially effective therapeutic approach for liver fibrosis.

Experimental procedure: C57BL/6 mice were fed a special diet containing 3,5-diethoxycarbonyl-1,4-dihydroxylidine (DDC) to induce liver fibrosis. The histopathological changes in liver tissue and intestinal mucosa were determining via immunohistochemical staining. Serum transaminase levels were determined using biochemical test kits. Faecalibaculum samples were sequenced via 16S rRNA sequencing.

Results: Cordycepin reduced DDC-induced liver collagen deposition, improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced the levels of endothelial dysfunction markers vascular cell adhesion molecule 1 (VCAM) and thrombomodulin (TM). Our analysis of the intestinal flora composition showed that Dubosiella, Faecalibaculum, and Bifidobacterium were significantly increased in the cordycepin-treated group (P < 0.05). The Dubosiella level was significantly negatively correlated with TM and VCAM levels, and serum levels of ALT and AST (P < 0.05). After treatment with cordycepin, the microvilli length in the intestinal mucosa, the density of goblet cells, and the expressions of occludin and zonula occludens protein 1 (ZO-1) were significantly increased (P < 0.05).

Conclusion: We discovered that cordycepin improves liver fibrosis in vivo. We found that Dubosiella levels were considerably increased in the cordycepin-treated group and were significantly negatively correlated with liver sinusoidal endothelial damage.

Keywords: Cordycepin; Intestinal flora; Intestinal mucosal barrier; Liver fibrosis.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Deoxyadenosines* / pharmacology
  • Gastrointestinal Microbiome* / drug effects
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis* / chemically induced
  • Liver Cirrhosis* / drug therapy
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Thrombomodulin / metabolism
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Deoxyadenosines
  • cordycepin
  • Alanine Transaminase
  • Aspartate Aminotransferases
  • Vascular Cell Adhesion Molecule-1
  • Thrombomodulin