Network pharmacology and experiments verify the effect of triptolide on extraocular muscle fibrosis
Minmin Jiang1, Ping Wang1, Dandan Yu1
1Department of Endocrinology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, China.
Abstract:
Drugs usually do not prevent extraocular muscle fibrosis in Graves' ophthalmopathy (GO), and surgical treatment has complications and does not cure extraocular muscle fibrosis. Triptolide (TPL) has shown antifibrotic effects; however, the mechanism by which it treats extraocular muscle fibrosis in GO remains unclear. The aim of this study was to investigate the therapeutic effect and potential mechanism of TPL through a combination of network pharmacology and experimental validation. Network pharmacology identified 10 potential therapeutic targets, 1767 gene ontology terms, and 95 signaling pathways, including the PI3K/AKT pathway. Molecular docking revealed a strong affinity between core targets on the PI3K/AKT pathway and TPL. The experimental results showed that TPL inhibited the proliferation of OFs in vitro in a concentration-dependent manner. It significantly inhibited the expression of TGF-β1-induced fibrosis-related markers, such as FN, CTGF, α-SMA, and TIMP-1, while significantly down-regulating the expression of PI3K/AKT signaling proteins. The use of inhibitors of the PI3K/AKT pathway inhibited the expression of fibrosis-related markers. These findings suggest that TPL can resist extraocular muscle fibrosis in GO through multiple pathways, in which the PI3K/AKT pathway plays a key role.
Insights
Triptolide (TPL) shows promise in treating Graves' ophthalmopathy (GO) fibrosis by inhibiting key cellular pathways. This study elucidates its mechanism, highlighting the PI3K/AKT pathway
Area of Science:
- Endocrinology
- Pharmacology
- Molecular Biology
Background:
- Graves' ophthalmopathy (GO) involves extraocular muscle fibrosis, often resistant to current drug therapies.
- Surgical interventions for GO have limitations and do not resolve underlying fibrosis.
Purpose of the Study:
- To investigate the therapeutic potential and mechanism of Triptolide (TPL) in treating extraocular muscle fibrosis in GO.
- To combine network pharmacology with experimental validation to understand TPL's action.
Main Methods:
- Network pharmacology identified potential therapeutic targets and signaling pathways, including PI3K/AKT.
- Molecular docking assessed the binding affinity of TPL to key targets.
- In vitro experiments validated TPL's effect on orbital fibroblast (OF) proliferation and fibrosis markers.
Main Results:
- TPL inhibited OF proliferation in a dose-dependent manner.
- TPL significantly reduced expression of fibrosis markers (FN, CTGF, α-SMA, TIMP-1) induced by TGF-β1.
- TPL down-regulated PI3K/AKT signaling proteins, and pathway inhibitors corroborated these effects.
Conclusions:
- TPL demonstrates antifibrotic effects in Graves' ophthalmopathy.
- The PI3K/AKT pathway is a key mediator of TPL's therapeutic action against extraocular muscle fibrosis in GO.
