MDP Induces the Senescence of Activated Hepatic Stellate Cells Through Regulating Ago2/miR-708/ZEB1/p53 Pathway

Background: Extracellular matrix (ECM) is mainly derived from activated hepatic stellate cells (HSC), and its excessive deposition is one of the characteristics of liver fibrosis. Accumulating evidence indicated that the senescence of activated HSCs limits liver fibrosis. Monomer derivative of paeoniflorin (MDP), a derivative of paeoniflorin, inhibits inflammatory responses. However, the role and fundamental mechanism of MDP in liver fibrosis was still unclear. Results We demonstrated that MDP inhibited the progression of liver fibrosis in vivo and in vitro, concomitant with the elevated expression of Ago2, miR-708 and p53 as well as the downregulated expression of ZEB1. Mechanistic investigations revealed that MDP could combined with Ago2, thus promoting the expression of miR-708. Upregulation of miR-708 and p53 and downregulation of ZEB1 increased the number of SA-β-Gal-positive HSCs and the expression levels of p16 and p21 as well as decreased the expression of α-SMA and Col. I in activated HSCs. Meanwhile, further studies revealed that miR-708 directly targeted ZEB1, thus inhibiting the mRNA of ZEB1. More importantly, ZEB1 could bind to the E-box of p53 promoter and restrain its promoter activity as well as thus block the expression of p53. Conclusion MDP could induce senescence of activated HSCs via regulating Ago2/miR-708/ZEB1/p53 aixs and may be applied to treat liver fibrosis.