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Mechanism of acacetin regulating hepatic stellate cell apoptosis based on network pharmacology and experimental
Xue Hu1, Haotian Shen1, Rong Liu1
1School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China.
Background:
Hepatic fibrosis is caused by various liver diseases and eventually develops into liver cancer. There is no specific drug approved for the treatment of hepatic fibrosis in the world. Acacetin (AC), a natural flavonoid, is widely present in nature in various plants, such as black locust, Damiana, Silver birch. It has been reported that acacetin can inhibit the proliferation of cancer cells and induce apoptosis.
Purpose:
In this study, we investigated the effect of acacetin on hepatic stellate cell apoptosis, thereby improving hepatic fibrosis, and combined experimental validation and molecular docking to reveal the underlying mechanism.
Result:
First, we discovered that acacetin inhibited hepatic stellate cell proliferation as well as the expression of fibrosis-related proteins α-smooth muscle actin (α-SMA) and collagen type I 1 gene (COL1A1) in LX2 cells. Acacetin was then found to promote apoptosis of hepatic stellate cells through the caspase cascade pathway. Network pharmacology screening showed that TP53, CASP3, CASP8, BCL2, PARP1, and BAX were the most important targets related to apoptosis in the PPI network. GO and KEGG analyses of these six important targets were performed, and the top 10 enriched biological processes and related signaling pathways were revealed. Further network pharmacology analysis proved that apoptosis was involved in the biological process of acacetin's action against hepatic stellate cells. Finally, molecular docking revealed that acacetin binds to the active sites of six apoptotic targets. In vitro experiments further confirmed that acacetin could promote the apoptosis of LX2 cells by inducing the activation of P53, thereby improving hepatic fibrosis.
Conclusion:
acacetin induces P53 activation and promotes apoptosis of hepatic stellate cells thereby ameliorating hepatic fibrosis.
Insights
Acacetin, a natural flavonoid, effectively reduces hepatic fibrosis by promoting apoptosis in hepatic stellate cells. This study reveals its mechanism involves P53 activation, offering a potential therapeutic strategy for liver disease.
Area of Science:
- Biochemistry
- Pharmacology
- Hepatology
Background:
- Hepatic fibrosis, a precursor to liver cancer, lacks specific treatments.
- Acacetin (AC), a natural flavonoid, exhibits anti-cancer properties.
- Investigating AC's role in hepatic fibrosis is crucial.
Purpose of the Study:
- To investigate acacetin's effect on hepatic stellate cell apoptosis.
- To elucidate the underlying molecular mechanisms of acacetin in ameliorating hepatic fibrosis.
- To combine experimental validation with molecular docking for comprehensive analysis.
Main Methods:
- Assessed acacetin's impact on LX2 cell proliferation and fibrosis markers (α-SMA, COL1A1).
- Investigated acacetin-induced apoptosis via the caspase cascade pathway.
- Employed network pharmacology, GO, KEGG, and molecular docking to identify key targets and pathways.
Main Results:
- Acacetin inhibited LX2 cell proliferation and reduced fibrosis protein expression.
- Acacetin promoted hepatic stellate cell apoptosis through caspase activation.
- Network pharmacology identified TP53, CASP3, CASP8, BCL2, PARP1, and BAX as key apoptotic targets.
Conclusions:
- Acacetin induces P53 activation, promoting hepatic stellate cell apoptosis.
- Acacetin demonstrates therapeutic potential for ameliorating hepatic fibrosis.
- Molecular docking confirmed acacetin's binding to key apoptotic targets.
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