Catalpol ameliorates liver fibrosis via inhibiting aerobic glycolysis by EphA2/FAK/Src signaling pathway.

Autor: Zhang Q; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: qingxiuzhang379@qq.com., Ran T; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: rantao.007@qq.com., Li S; Department of Vascular Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: ainia1694@qq.com., Han L; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: 138910318@qq.com., Chen S; Guizhou Medical University, Guiyang 550000, China. Electronic address: chenshaojie@stu.gmc.edu.cn., Lin G; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: 1156124413@qq.com., Wu H; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: wuhuayue156@163.com., Wu H; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: gmu-wuhuan@qq.com., Feng S; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: 15121210573@163.com., Chen J; Clinical Trials Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: chenjiyu@gmc.edu.cn., Zhang Q; Department of Nephrology, The Guizhou provincial people's Hospital, Guiyang 550000, China. Electronic address: 782797854@qq.com., Zhao X; Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: zhaoxueke1@163.com.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2024 Dec; Vol. 135, pp. 156047. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1016/j.phymed.2024.156047
Abstrakt: Background: Hepatic fibrosis is a pathological process in a variety of acute or chronic liver injuries. Catalpol (CAT), an iridoid glycoside found in Rehmannia glutinosa, has several pharmacological properties, including anti-inflammatory, antidiabetic and anti-fibrotic effects. Nevertheless, there is currently no report on whether CAT regulates the aerobic glycolysis of hepatic stellate cells (HSCs) to inhibit liver fibrosis.
Objective: This study aimed to investigate the protective effects of CAT on hepatic fibrosis and elucidate its underlying mechanisms.
Methods: To explore whether CAT improved liver fibrosis in vivo and in vitro, hepatic fibrosis was induced to mice by intraperitoneally injecting carbon tetrachloride (CCl 4 ). Additionally, LX-2 cells were stimulated with transforming growth factor-β (TGF-β) to simulate fibrosis in vitro. Serum markers of liver injury were examined by using an automatic biochemical analyzer. Histopathological staining, Immunofluorescence (IF) staining, Western blot (WB) analysis, co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), etc. were employed to identify the targeting between CAT and EphA2 and detect the expression of aerobic glycolysis related proteins, fiber markers and signaling pathways that are responsible for CAT's anti-fibrotic effects of CAT.
Results: Results showed that CAT significantly inhibited hepatic injury, fibrogenesis and inflammation in mice treated with CCl 4 . This was demonstrated by the enhancement of fibrosis markers, liver function indices, and histopathology. In addition, CAT significantly inhibited the activation of HSCs in TGF-β-induced LX-2 cells, as indicated by decreased proliferation, migration, and expression of collagen I and a-SMA. The study results also suggested that CAT may exert anti-fibrotic effects by inhibiting glycolysis in activated HSCs and in CCl 4 -treated mice. Mechanistically, CAT directly targets Ephrin type-A receptor 2 (EphA2) to reduce binding with focal adhesion kinases (FAK) and significantly inhibits the FAK/Src pathway. In addition, the pharmacological inhibition of EphA2 cannot further increase the therapeutic effects of CAT on liver fibrosis in vivo and in vitro.
Conclusion: The study findings generally demonstrated that CAT presented a novel therapeutic method to treat hepatic fibrosis; this method which inhibits the aerobic glycolysis of activated HSCs through the EphA2/FAK/Src signaling pathway.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier GmbH. All rights reserved.)
Databáze: MEDLINE
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