A network pharmacology approach-based decoding of Resveratrol's anti-fibrotic mechanisms

Phytomedicine. 2024 Dec:135:156092. doi: 10.1016/j.phymed.2024.156092. Epub 2024 Sep 28.

Abstract

Background: Inhalation of crystalline silica (CS) frequently leads to chronic lung inflammation and pulmonary fibrosis (PF), a condition with limited effective treatments. Resveratrol (Res) has demonstrated potential in PF treatment; however, its underlying mechanisms remain incompletely elucidated.

Purpose: This study represents the first comprehensive attempt to uncover the novel mechanisms underlying Res's anti-fibrotic effects against PF through an innovative, integrated approach combining network pharmacology and experimental validation.

Methods: We employed network pharmacology to investigate the holistic pharmacological mechanism of Res, then validated the predicted pharmacological effects using in vivo and in vitro studies.

Results: In total, 216 genes were identified to be simultaneously associated with PF and Res. An integrated bioinformatics analysis implicated a crucial role of the autophagy signaling pathway in dominating PF, with AMPK and mTOR showing high docking scores. Animal studies revealed that Res significantly alleviated silica-induced lung damage in silicotic mice, with decreased collagen I (Col-I) levels and reduced expression of vimentin and α-SMA. In-depth investigation demonstrated that Res modulated CS-dysregulated autophagy by targeting the AMPK/mTOR pathway. in vitro, Res treatment significantly reduced lactate dehydrogenase (LDH), TNF-α, and TGF-β levels and improved cell viability of Raw264.7 cells post-CS exposure. Notably, Res was demonstrated to suppress fibroblast-to-myofibroblast transition via mediating macrophage autophagy through the AMPK/mTOR pathway.

Conclusion: Res can alleviate CS-induced PF by targeting AMPK in the autophagy signaling pathway, which sheds light on Res' therapeutic potential in treating PF.

Keywords: AMPK/mTOR; Network pharmacology; Pulmonary fibrosis; Res; Silicosis.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antifibrotic Agents / pharmacology
  • Autophagy* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Network Pharmacology*
  • Pulmonary Fibrosis* / drug therapy
  • RAW 264.7 Cells
  • Resveratrol* / pharmacology
  • Signal Transduction / drug effects
  • Silicon Dioxide
  • TOR Serine-Threonine Kinases* / metabolism

Substances

  • Resveratrol
  • TOR Serine-Threonine Kinases
  • Silicon Dioxide
  • AMP-Activated Protein Kinases
  • Antifibrotic Agents