ABSTRACT
TGFß1 signaling pathway is associated with many diseases, which can induce the activation of hepatic stellate cells (HSCs) and induce liver fibrosis. Studies have shown that 20S-protopanaxadiol (PPD) has a therapeutic effect on liver fibrosis, but the target is unknown. In this study, we confirmed that PPD reduced the mRNA expression of downstream genes of the TGFß1 pathway, which suggesting PPD is associated with the TGFß1 pathway. The protein dissociation temperature and dissociation constant (Kd) of PPD on TGFßR1 and TGFßR2 were determined, which showed that PPD combined with TGFßR1 (Kd = 1.54 µM). The docking and simulation methods were used to find their binding sites. Site mutations, protein expression and in vitro binding experiments were performed to demonstrated these sites. In particular, these sites of TGFßR1 were also the active sites of TGFßR2. Therefore, we speculated that PPD blocked the combination of TGFßR1 and TGFßR2 by binding to the D57, R58, P59, and N78 of the TGFßR1 extracellular domain. Thus, PPD could block the transmission of TGFß1 pathway and inhibit the activation of HSCs, and treating fibrosis. Our studies showed that PPD has the potential to treat diseases related to the TGFß1 pathway and broadens its clinical application.
