Rehmannioside D ameliorates hepatocyte apoptosis and liver fibrosis by suppressing Sirt7/p53 axis

The traditional Chinese herb Rehmannia glutinosa (Gaertn.) DC. is an extensively employed to manage liver diseases. Rehmannioside D (RD), a major bioactive constituent of Rehmannia glutinosa (Gaertn.) DC, exhibits significant anti-apoptotic properties. Nevertheless, its efficacy and underlying mechanisms against hepatic fibrosis remain poorly defined.

To evaluate the pharmacological effects of RD on liver fibrosis and elucidate its underlying mechanisms of action.

In vivo, the therapeutic efficacy of RD was evaluated in two classical liver fibrosis models: CCl₄-treated mice and DMN-exposed rats. In vitro, RD's impact on hepatocyte apoptosis and the contribution of Sirtuin 7 (Sirt7) were investigated in H₂O₂-injured AML12 cells, using a selective Sirt7 inhibitor.

RD treatment demonstrated a systematic reduction in hepatic injury, inflammation, and collagen deposition in vivo fibrosis models. RNA-sequencing analysis revealed that the therapeutic effects of RD was closely related to suppression of the p53 signaling pathway and cellular apoptosis. Similarly, RD significantly alleviated hepatocyte apoptosis in fibrotic livers, and this anti-apoptotic effect was mediated through the Sirt7/p53 signaling axis. In vitro, RD alleviated H₂O₂-induced apoptosis in AML12 cells, however, this protective effect was partially abrogated by pharmacological inhibition of Sirt7.

Collectively, these findings indicated that RD attenuates hepatic fibrosis by upregulating Sirt7 expression, thereby inhibiting acetyl-p53-mediated hepatocyte apoptosis. Collectively, our findings establish RD as a promising anti-fibrotic agent and identify the Sirt7/p53 axis as its key mechanistic conduit.