Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation

Saikosaponin b1 (Ssb1), a natural oleanane-type triterpenoid saponin, exhibits antifibrosis activity by inhibiting the activation of hepatic stellate cells (HSCs), but the specific underlying molecular mechanisms are unknown. Here, it is found that Ssb1 could directly bind with the signal transducer and activator of transcription 3 (STAT3) and effectively inhibit the activation of HSCs. Proteomic techniques and molecular simulation revealed that Ssb1 is mainly bound to the S319 residues of STAT3 in the coiled-coil domain. Further studies indicated that Ssb1 binding with STAT3 inhibited its transcriptional activity, and regulated glioma-associated oncogene-1 (Gli1) expression in the Hedgehog signaling pathway. Besides, Ssb1 binding blocked interaction between STAT3 and Gli1, which promoted degradation of Gli1 protein by suppressor of fused homolog (SUFU) and the ubiquitin-proteasome system. The loss function of Gli1 led to decreased expression of Bcl2 and promoted the apoptosis of activated HSCs. Moreover, STAT3 ablation abolished the Ssb1-mediated antifibrotic effects. These findings show that STAT3 plays a vital role in Ssb1 treatment of liver fibrosis, and Ssb1 as a STAT3 inhibitor might be a promising therapeutic candidate for the treatment of hepatic fibrosis.