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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 (CCl4) 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.<\/jats:p>","DOI":"10.3390\/ph16040548","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T01:10:27Z","timestamp":1680743427000},"page":"548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis"],"prefix":"10.3390","volume":"16","author":[{"given":"Qilin","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China"},{"name":"National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China"},{"name":"Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China"},{"name":"Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 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