Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis
Liver fibrosis represents a significant health hazard with a high morbidity rate and an increased risk of liver cancer. Targeting overactivated Fibroblast growth factor receptor 2 (FGFR2) is a promising strategy to counteract collagen accumulation during liver fibrosis. However, there is a shortage...
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MDPI AG
2023-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/4/548 |
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| author | Qilin Meng Lin Luo Minghua Lei Zhiqi Chen Yuanmeng Sun Xue Chen Zhaodong Zhai Yibo Zhang Jieqiong Cao Zijian Su Fu Li Jingsheng Li An Hong Xiaojia Chen |
| author_facet | Qilin Meng Lin Luo Minghua Lei Zhiqi Chen Yuanmeng Sun Xue Chen Zhaodong Zhai Yibo Zhang Jieqiong Cao Zijian Su Fu Li Jingsheng Li An Hong Xiaojia Chen |
| author_sort | Qilin Meng |
| collection | DOAJ |
| description | Liver fibrosis represents a significant health hazard with a high morbidity rate and an increased risk of liver cancer. Targeting overactivated Fibroblast growth factor receptor 2 (FGFR2) is a promising strategy to counteract collagen accumulation during liver fibrosis. However, there is a shortage of drugs to specifically block the activation of FGFR2 in liver fibrosis patients. Data mining, cell validation, and animal studies showed a positive correlation between FGFR2 overexpression and liver fibrosis development. Novel FGFR2 inhibitors were screened using a microarray-based high-throughput binding analysis. The effectiveness of each candidate was validated through simulated docking, binding affinity verification, single-point mutation validation, and in vitro kinase inhibition measurements to demonstrate the ability of each inhibitor to block the catalytic pocket and reverse FGFR2 overactivation. A specific FGFR2 inhibitor, cynaroside (CYN, also known as luteoloside), was screened based on the finding that FGFR2 promotes hepatic stellate cell (HSC) activation and collagen secretion in hepatocytes. The results from cellular assays showed that CYN can inhibit FGFR2 hyperactivation resulting from its overexpression and excessive basic fibroblast growth factor (bFGF), reducing HSC activation and collagen secretion in hepatocytes. Animal experiments on a carbon tetrachloride (CCl<sub>4</sub>) mouse model and a nonalcoholic steatohepatitis mouse model indicate that CYN treatment reduces liver fibrosis during fibrosis formation. These findings suggest that CYN prevents liver fibrosis formation at the cell level and in mouse models. |
| first_indexed | 2024-03-11T04:39:20Z |
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| id | doaj.art-6d540c09df4f4ee9b6fb75600670a54f |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T04:39:20Z |
| publishDate | 2023-04-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-6d540c09df4f4ee9b6fb75600670a54f2023-11-17T20:50:30ZengMDPI AGPharmaceuticals1424-82472023-04-0116454810.3390/ph16040548Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver FibrosisQilin Meng0Lin Luo1Minghua Lei2Zhiqi Chen3Yuanmeng Sun4Xue Chen5Zhaodong Zhai6Yibo Zhang7Jieqiong Cao8Zijian Su9Fu Li10Jingsheng Li11An Hong12Xiaojia Chen13Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaDepartment of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, ChinaLiver fibrosis represents a significant health hazard with a high morbidity rate and an increased risk of liver cancer. Targeting overactivated Fibroblast growth factor receptor 2 (FGFR2) is a promising strategy to counteract collagen accumulation during liver fibrosis. However, there is a shortage of drugs to specifically block the activation of FGFR2 in liver fibrosis patients. Data mining, cell validation, and animal studies showed a positive correlation between FGFR2 overexpression and liver fibrosis development. Novel FGFR2 inhibitors were screened using a microarray-based high-throughput binding analysis. The effectiveness of each candidate was validated through simulated docking, binding affinity verification, single-point mutation validation, and in vitro kinase inhibition measurements to demonstrate the ability of each inhibitor to block the catalytic pocket and reverse FGFR2 overactivation. A specific FGFR2 inhibitor, cynaroside (CYN, also known as luteoloside), was screened based on the finding that FGFR2 promotes hepatic stellate cell (HSC) activation and collagen secretion in hepatocytes. The results from cellular assays showed that CYN can inhibit FGFR2 hyperactivation resulting from its overexpression and excessive basic fibroblast growth factor (bFGF), reducing HSC activation and collagen secretion in hepatocytes. Animal experiments on a carbon tetrachloride (CCl<sub>4</sub>) mouse model and a nonalcoholic steatohepatitis mouse model indicate that CYN treatment reduces liver fibrosis during fibrosis formation. These findings suggest that CYN prevents liver fibrosis formation at the cell level and in mouse models.https://www.mdpi.com/1424-8247/16/4/548liver fibrosiscollagen accumulationFGFR2cynarosidehepatic stellate cells |
| spellingShingle | Qilin Meng Lin Luo Minghua Lei Zhiqi Chen Yuanmeng Sun Xue Chen Zhaodong Zhai Yibo Zhang Jieqiong Cao Zijian Su Fu Li Jingsheng Li An Hong Xiaojia Chen Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis Pharmaceuticals liver fibrosis collagen accumulation FGFR2 cynaroside hepatic stellate cells |
| title | Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis |
| title_full | Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis |
| title_fullStr | Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis |
| title_full_unstemmed | Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis |
| title_short | Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis |
| title_sort | inhibition of fgfr2 signaling by cynaroside attenuates liver fibrosis |
| topic | liver fibrosis collagen accumulation FGFR2 cynaroside hepatic stellate cells |
| url | https://www.mdpi.com/1424-8247/16/4/548 |
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