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

被引:2
作者
Zhang, Qingxiu [1 ]
Ran, Tao [1 ]
Li, Shiliang [2 ]
Han, Lu [1 ]
Chen, Shaojie [3 ]
Lin, Guoyuan [1 ]
Wu, Huayue [1 ]
Wu, Huan [1 ]
Feng, Shu [1 ]
Chen, Jiyu [4 ]
Zhang, Qian [5 ]
Zhao, Xueke [1 ]
机构
[1] Guizhou Med Univ, Affiliated Hosp, Dept Infect Dis, Guiyang 550000, Peoples R China
[2] Guizhou Med Univ, Affiliated Hosp, Dept Vasc Surg, Guiyang 550000, Peoples R China
[3] Guizhou Med Univ, Guiyang 550000, Peoples R China
[4] Guizhou Med Univ, Affiliated Hosp, Clin Trials Ctr, Guiyang 550000, Peoples R China
[5] Guizhou Prov Peoples Hosp, Dept Nephrol, Guiyang 550000, Peoples R China
关键词
Catalpol; Hepatic fibrosis; Hepatic stellate cells; Aerobic glycolysis; EphA2/FAK/Src signaling pathway; STELLATE; ACTIVATION; EXPRESSION; MEDIATORS; GROWTH; CELLS;
D O I
10.1016/j.phymed.2024.156047
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
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 (CCl4). Additionally, LX-2 cells were stimulated with transforming growth factor-beta (TGF-beta) 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 CCl4. 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-beta-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 CCl4-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.
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页数:15
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