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OBJECTIVE Hepatic stellate cells (HSC) play a critical role in development of liver fibrosis, since these cells are the principal cellular source of the excess collagen synthesis.The present study was designed to investigate the effects of paeoniflorin, a monoterpene glucoside, on the proliferation of hepatic stellate ceils (HSC).Furthermore, the roles of G protein-coupled signalling and its key modulators G protein-coupled receptor kinases (GRK) in hepatic fibrosis were also investigated to further elucidate the anti-proliferation mechanism of paeoniflorin.METHODS HSC were cultured in platelet derived growth factor-BB (PDGF-BB) with or without different concentrations of paeoniflorin.The proliferation of HSC was measured by MTT assay.The level of cAMP in HSC was determined by radioimmunoassay.The expression of G protein, GRK2 of HSC were detected by Western blot analysis.RESULTS Paeoniflorin significantly inhibited the proliferation of HSC stimulated with PDGF-BB.The expression of Gαi-1 and C αi-2 were remarkably increased in HSC stimulated by PDGF-BB, but the expression of Gαi-3 and Gαs had no significant change.Meanwhile, the level of cAMP and the activity of PKA in HSC were obviously decreased.High levels of Gαi-1 and Gαi-2 and decreased level of cAMP were restored with paeoniflorin administration.The role of GRK2, a key modulator of G protein-coupled signalling, in liver fibrosis was further investigated in this study.The results showed that aggravation of hepatic fibrosis led to gradually decreasing expression of GRK2 in HSC.When GRK2 inhibitor was given to decrease expression of GRK2, paeoniflorin remarkably increased the expression of GRK2 and decreased G αi-1, Gαi-2 expression in membrane fractions of HSC stimulated with PDGF-BB.The expression of Gαs also had no significant change all along.CONCLUSION Our findings suggest that the down-regulated expression of GRK2 in HSC correlates with hepatic fibrosis.Paeoniflorin had inhibitory effect on the proliferation of HSC, which due to upregulating membrane GRK2 and decrease Gi coupled signalling.These results indicate that paeoniflorin have therapeutically potential for the treatment of liver fibrosis.