Cajanonic acid A derivative XJ-60 improves liver fibrosis in mice with non-alcoholic fatty liver disease by inhibiting the SP1/TGF-β/Smad3 signaling axis
GENG Zhaodie
HU Li
DAI Yunli
LUO Ronggang
XU Tao
LIAO Xuyang
YUAN Zhiping
WANG Jianta
XIAO Ying
Abstract：Objective To investigate the mechanism of XJ-60,a derivative of cajanonic acid A,for alleviating liver fibrosis in mice with non-alcoholic fatty liver disease(NAFLD).Methods Twelve db/db mice were randomized equally into NAFLD model group and XJ-60 treatment group with daily gavage of 50 mg/kg XJ-60,with 6 db/m mice serving as the control group.Successful modeling of NAFLD was validated using HE and Oil Red O staining and by measuring ALT and AST levels of the mice.Immunohistochemistry was used for detecting hepatic expressions of specific protein 1(SP1)and fibronectin(FN);the changes in hepatic expressions of epithelial-mesenchymal transition(EMT)markers,extracellular matrix(ECM)markers,and IL-6 were detected using Western blotting and ELISA.In AML12 cells induced with free fatty acids(FFA),the effect of XJ-60 on expressions of SP1,transforming growth factor-β(TGF-β),Smad3/p-Smad3,and the markers of EMT and ECM were analyzed.SP1 knockdown experiment was performed to validate the role of TGF-β/Smad3 signaling axis in NAFLD.Results XJ-60 treatment significantly reduced serum lipid levels,improved liver histology,and lowered hepatic IL-6 expression in db/db mice.The expression level of SP1 was positively correlated with α-SMA and negatively with E-ca expression.In AML12 cells,XJ-60 treatment at 10 μmol/L significantly reduced FFA-induced lipid accumulation and downregulated cellular expressions of SP1,TGF-β,p-Smad3,and the EMT and ECM markers;SP1 knockdown obviously inhibited the expression levels of TGF-β,Smad3 and ECM markers.Conclusion XJ-60 ameliorates liver fibrosis and steatosis in mice with NAFLD possibly through SP1-mediated inhibition of the TGF-β/Smad3 pathway to reduce ECM deposition.
Keywords：non-alcoholic fatty liver diseasespecific protein 1transforming growth factor-βSmad3 proteincajanonic acid A derivative
Publication Date：2026-02-20
Online Publishing Date：2026-03-04(First online date of this platform, not the publication date of the document)
Pages：12( 362-373 )