Ginsenoside PPD inhibit the activation of HSCs by directly targeting TGF13R1

TGF131 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 TGF131 pathway, which suggesting PPD is associated with the TGF131 pathway. The protein dissociation temperature and dissociation constant (Kd) of PPD on TGF13R1 and TGF13R2 were determined, which showed that PPD combined with TGF13R1 (Kd = 1.54 mu M). 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 TGF13R1 were also the active sites of TGF13R2. Therefore, we speculated that PPD blocked the combination of TGF13R1 and TGF13R2 by binding to the D57, R58, P59, and N78 of the TGF13R1 extracellular domain. Thus, PPD could block the transmission of TGF131 pathway and inhibit the activation of HSCs, and treating fibrosis. Our studies showed that PPD has the potential to treat diseases related to the TGF131 pathway and broadens its clinical application.

Automated summary

PPD blocks the transmission of the TGF131 pathway, inhibits the activation of HSCs, and has the potential to treat diseases related to the TGF131 signaling pathway.