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Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis
Tung-Hung Su1,2,3, Chung-Wai Shiau4, Ping Jao1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan.
Abstract:
This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)-signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1-STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery.
Insights
A novel SHP-1 agonist, SC-43, effectively treats liver fibrosis by targeting the SHP-1-STAT3 pathway. This drug promotes hepatic stellate cell apoptosis and inhibits proliferation, offering a promising antifibrotic therapy.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Liver fibrosis is a significant health concern.
- The src-homology protein tyrosine phosphatase-1 (SHP-1)-signal transducer and activator of transcription 3 (STAT3) pathway plays a role in liver fibrogenesis.
Purpose of the Study:
- To investigate the role of the SHP-1-STAT3 pathway in liver fibrogenesis.
- To evaluate the anti-fibrotic effect of SC-43, a SHP-1 agonist.
Main Methods:
- SC-43's antifibrotic activity was tested in carbon tetrachloride-induced and bile duct ligation liver fibrosis mouse models.
- Mechanistic studies utilized rat, human, and primary mouse hepatic stellate cells (HSCs).
- SHP-1 activity, STAT3 phosphorylation, HSC apoptosis, and proliferation were assessed.
Main Results:
- SHP-1 protein was found in fibrotic areas of human and mouse livers.
- SC-43 treatment reduced activated HSCs, preventing and regressing liver fibrosis and improving survival in mice.
- In vitro, SC-43 enhanced SHP-1 activity, inhibited phospho-STAT3, promoted HSC apoptosis, and inhibited HSC proliferation.
Conclusions:
- The SHP-1-STAT3 pathway is critical in liver fibrogenesis.
- SC-43 ameliorates liver fibrosis by upregulating SHP-1 activity.
- Targeting SHP-1 offers a potential therapeutic strategy for antifibrotic drug discovery.
