Transforming growth factor-\(\beta\)1 (TGF-\(\beta\)1), a key cytokine, is involved in the formation of liver fibrosis. TGF-\(\beta\)1 directly induces collagen 1 and \(\alpha\)-smooth muscle actin (\(\alpha\)-SMA) expressed in HSCs through a phosphorylation of downstream Smad2/3 proteins [11; 12; 13]. TGF-\(\beta\)1 also enhances the ECM proteins synthesis and restrains their degradation [14]. Blocking the TGF-\(\beta\)1 signaling transduction obviously inhibits liver fibrosis [15; 16]. In terms of TGF-\(\beta\)1, platelet-derived growth factor-BB (PDGF-BB) and VEGF released from activating HSCs are important factors for sustaining activation and proliferation of HSCs [7]. Previous studies had found that dysregulated PDGF-BB signaling pathway is the major inducement for the HSCs trans-differentiation, and also an important pathological factor for liver fibrosis [17]. PDGF-BB activates Ras, subsequently propagating stimulatory signaling via phosphorylation of the MAPK and Akt signaling pathways [11]. Blockade of PDGF signaling reduced experimental liver fibrogenesis [17]. The inhibition of TGF-\(\beta\)1 and blockade of Akt/P70S6K axis, as well as ERK signaling, have been proven to alleviate HSC activation [18; 19]. Natural plants have been used as the major source of food and medicine worldwide for thousands of years. Chinese herbs are an abundant resource, and have promising application prospects for treating different diseases. Paeonol (a phenolic) is the main active element of Cortex Moutan, which is used in traditional Chinese herbal medicine. Ample pharmacological evidence suggests that paeonol has a lot of biological functions, including antioxidant, anti-inflammatory, antitumor, antidiabetic, anti-cardiovascular disease, and neuroprotective effects [20; 21]. Paeonol enhanced the apoptosis of ovarian tumor cells by decreasing surviving expression and initiating activity of caspase 3 [22]. Paeonol also had a radio-enhancing effect on lung adenocarcinoma [23] and attenuated acute lung injury in lipopolysaccharide-induced shock rats [24]. Additionally, paeonol has shown anti-alcoholic fatty liver [25] and anti-liver cancer [26] activities. Because of the pharmacological and physiological significances of paeonol for treatment of different diseases, some paeonol derivatives have been synthesized, and these compounds have considerable drug discovery potential in medicinal chemistry [21]. The introduction of a phenylsulfonyl moiety into a compound was found to improve the solubility of the compound and enhance its biological activity [27; 28]. Previously, we designed a series of paeonol-phenylsulfonyl derivatives and found that 4-methoxy sulfonyl paeonol (4-MSP) (Figure 1a) significantly inhibits HBV gene expression and viral DNA replication [29]. However, the antifibrotic effects of 4-MSP in the liver are still unknown. In this study, we showed that 4-MSP exerts antifibrotic effects by suppressing TGF-\(\beta\)1/Smad, PDGF-BB/MAPK, and Akt signaling, both in cells and in the mouse model. Figure 1: Compound 4-MSP inhibits TGF-\(\beta\)1-induced hepatic stellate cells (HSCs) activation. (**a**) Structure of 4-methoxy sulfonyl paeanol (4-MSP). (**b**) LX2 cells were treated with TGF-\(\beta\)1 (10 ng/mL) and 4-MSP for 24 h. Western blot analyzed the protein levels of \(\alpha\)-SMA, col1A1, and \(\alpha\)-tubulin. (**c**) Real-time PCR detected mRNA levels of \(\alpha\)-SMA and col1A2 relative to that of GAPDH. *: \(p<0.05\) vs. TGF-\(\beta\)1 alone group; **: \(p<0.01\) vs. TGF-\(\beta\)1 alone group. (**d**) LX2 cells were treated with 4-MSP for 24 h. Western blot analyzed the protein levels of \(\alpha\)-SMA, col1A1, and \(\alpha\)-tubulin. (**e**) Real-time RT-PCR detected mRNA levels of \(\alpha\)-SMA and col1A2 relative to that of GAPDH. *: \(p<0.05\) vs. control group; **: \(p<0.01\) vs. control group. (**f**) HSC-T6 cells were treated with TGF-\(\beta\)1 (10 ng/mL) and 4-MSP for 24 h. Western blot analyzed the protein levels of \(\alpha\)-SMA, col1A1, and \(\alpha\)-tubulin.