## 4 Discussion  
Liver cirrhosis is a serious health issue worldwide which is usually correlated with an economic burden [32]. Furthermore, to prevent the progression of fibrosis that leads to cirrhosis is critical to improving the life quality of patients. When the liver is exposed to dangerous stimulations, normal HSCs are transdifferentiated from the quiescent type into active myofibblasts that are responsible for the extracellular matrix proteins expression and secretion, including collagen, elastin, proteoglycans, and some of the glycoproteins [33]. The activation of HSCs is considered a key phenomenon in the progression of liver fibrosis; hence, preventing an activation of HSCs is a promising strategy for liver fibrosis treatment. Cortex Moutan, a traditional herbal medicine, is popularly used to treat a lot of diseases worldwide. Paeonol is a phenolic compound and a major active component isolated from Cortex Moutan [21]. Paeonol has been approved by the China FDA, and its pharmacological effects are used to treat various diseases, including tumors, inflammatory diseases, cardiovascular diseases, and neurological diseases [20]. When the treatment of liver cancer with paeonol was examined, paeonol not only decreased oxidative injury and improved immune function in HCC rats [26], but also reversed endoplasmic reticulum stress-induced doxorubicin resistance in HCC [34]. In addition, paeonol treatment was found to alleviate drug- and alcohol-induced acute liver failure [35; 36] and steatohepatitisitis [25; 37], through inhibiting oxidative stress and inflammation. Since paeonol has been widely used in clinical applications for treating various types of disease, several paeonol derivatives with considerable drug discovery potential in medicinal chemistry have been synthesized [21]. The introduction of a phenylsulfonyl moiety into a compound was found to improve the solubility of the compound and increase its biological activity [27; 28]. Previously, we designed a series of paeonol-phenylsulfonyl derivatives, and showed that 4-MSP significantly inhibits HBV viral gene expression and viral DNA synthesis [29]. Regarding the treatment of liver fibrosis, paeonol has been found to inhibit HSC activation and fibrogenesis [38; 39]. In our study, significant antifibrotic effects were observed following treatment with the paeonol-phenylsulfonyl derivative 4-MSP at a lower dosage than that required for paeonol. While [PERSON] et al. reported that 10 uM and 100 mg/kg paeonol could inhibit HSC activation and liver fibrosis, respectively [38], we have shown that 4-MSP inhibits HSC activation and CCl\({}_{4}\)-induced liver fibrosis when applied at concentrations of 5 uM and 5 mg/kg, respectively. In addition, 4-MSP-treated mice exhibited no adverse events in terms of body weight loss, hepatotoxicity, or liver dysfunction, suggesting that treatment with 4-MSP is a novel therapeutic option for liver cirrhosis patients. In addition, paeonol administration has been found to prevent other models of fibrosis, such as pulmonary fibrosis and renal fibrosis, via regulating MAPK/Smad, Nrf2/ARE, and Notch1 pathways [40; 41; 42]. Except for CCl\({}_{4}\)-induced liver fibrosis, the bile duct ligation (BDL) is used to induce obstructive cholestatic injury. BDL promotes the growth of bile duct epithelial cells and portal inflammation, resulting in biliary-type liver fibrogenesis [5]. Activated bile duct epithelial cells synthesize matrix proteins and secret inflammatory mediators (TGF-b, IL-6, MCP1, and PDGF-BB) to activate HSCs. In Figure 5, we showed that 4-MSP expresses its anti-inflammatory potential to inhibit the expression of TNF-\(\alpha\) and F4/80. Accordingly, we considered that 4-MSP administration can also attenuate BDL-induced liver damage and fibrosis. The molecular aims of liver fibrosis therapy are the (1) attenuation of tissue damage and inflammation, (2) inhibition of HSCs' proliferation and activation, (3) induction of HSCs' apoptosis, and (4) promotion of ECM degradation [15; 43].