Chikusetsusaponin IVa targeted YAP as an inhibitor to attenuate liver fibrosis and hepatic stellate cell activation.

BACKGROUND: Liver fibrosis is a representative scarring response that can ultimately lead to liver cancer. However, relevant antifibrotic drugs for the effective treatment of liver fibrosis in humans have not yet been identified. Chikusetsusaponin IVa (CS-IVa) is derived from natural products and exhibits multiple biological activities; however, its efficacy and potential mechanism of action against liver fibrosis remains unclear. PURPOSE: This study aimed to examine the antifibrotic properties and potential mechanisms of action of CS-IVa. METHODS: We constructed two mature mouse models (CCl(4) challenge and bile duct ligation) to evaluate the antifibrotic properties of CS-IVa in vivo. Proteomics analysis and transforming growth factor β1 (TGF-β1)-activated LX-2 cells were used to elucidate the potential effects and mechanisms. Molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to detect the affinity and binding between CS-IVa and its target. RESULTS: We found that CS-IVa significantly alleviated liver fibrosis and injury by downregulating yes-associated protein (YAP) and tafazzin (TAZ) expression. In an in vitro model, CS-IVa suppressed TGF-β1-induced hepatic stellate cell (HSC) activation, as well as the mRNA and protein expression of COL1A1, α-SMA, YAP, and TAZ. Moreover, specific knockdown or inhibition of YAP did not enhance the suppressive effect of CS-IVa on HSC activation or fibrosis-associated protein expression. Molecular docking, SPR, and CETSA showed that CS-IVa could directly bind to YAP. CONCLUSION: These findings demonstrated that the administration of CS-IVa effectively alleviated liver fibrosis by suppressing the YAP/TAZ pathways. In addition, CS-IVa could directly bind to YAP and act as a YAP inhibitor.