4-methoxy sulfonyl paeonol inhibits hepatic stellate cell activation and liver fibrosis by blocking the TGF-β1/Smad, PDGF-BB/MAPK and Akt signaling pathways

Liver fibrosis initiates the progression of cirrhosis, and, finally, hepatocellular carcinoma (HCC). The increased proliferation and activation of hepatic stellate cells (HSCs) are crucial for hepatic fibrogenesis. Paeonol is the major vigorous component of Cortex Moutan, a traditional herbal medicine widely used for treating various diseases. Here, we identified a novel paeonol derivative (4-methoxy sulfonyl paeonol, 4-MSP) that inhibits TGF-β1-induced Smad2/3 phosphorylation and collagen expression in HSCs. 4-MSP pretreatment suppressed the PDGF-BB-induced phosphorylation of MAPK pathway members (MEK/ERK, p38, JNK), Akt/p70S6K, and HSC proliferation. However, 4-MSP treatment had no effect on the induction of apoptosis in HSCs. The microarray experiments showed that 4-MSP treatment affects the TGF-β signaling, MAPK cascade, and other pathways related to HSCs activation and proliferation. The administration of 4-MSP to a liver fibrosis mouse model induced by CCl4 significantly decreased the expression of hepatic fibrosis markers (a-SMA, col1A2, TGF-β, and MMP2), and attenuated hepatic collagen deposition and liver damage. In addition, no adverse effects were observed in 4-MSP exposed mice. In conclusion, this novel paeonol-phenylsulfonyl derivative prevents the progression of liver fibrosis through blocking TGF-β1/Smad, PDGF-BB/MAPK, and Akt signaling, which suggests its use as a novel therapeutic against liver fibrosis.