*2.1. Targeting HSCs*

Comprising about 13% of total liver cells, HSCs exist in the sinus space and come in direct contact with hepatic epithelial cells and endothelial cells [25]. In their normal state, HSCs are quiescent and mainly participate in vitamin A (VA) metabolism and fat storage. If the liver suffers from injuries, HSCs are activated and transformed into myofibroblasts. Activation of HSCs is a hallmark of liver fibrosis. Activated HSCs typically express smooth muscle actin (α-SMA); in addition, they synthesize and secrete the extracellular matrix (ECM). ECM deposition changes the structure and function of liver tissue, which is the root cause of liver fibrosis [26,27]. Therefore, activated HSCs are among the important targets for liver fibrosis therapy. Numerous signaling molecules are involved in the activation of HSCs, with TGF-β and PDGF being the important ones [27–29]. Therefore, blocking the TGF-β or PDGF signaling pathways is an effective strategy for the treatment of liver fibrosis. Protease inhibitors, such as camostat mesilate (FOY305), can neutralize TGF-β [30]. As a multi-target receptor tyrosine kinase inhibitor, sorafenib, targets the Raf/ERK signaling pathways and PDGF receptor and can effectively attenuate experimental liver fibrosis, inflammation, and angiogenesis [31]. Moreover, many anti-fibrosis drugs, such as the semisynthetic analog of fumagillin-TNP-470 [32] and the fungal metabolite-OPC-15161 [33], suppress the activation and proliferation of HSCs. Moreover, ROS contributes to liver fibrosis by promoting the activation and proliferation of fibroblasts and myofibroblasts, as well as the activating the TGF-β pathway in an autocrine manner [34]. Antioxidants, such as vitamin E [35], silymarin [36], N-acetylcysteine [8], resveratrol [37], quercetin [9], phosphatidylcholine [38], and glutathione [39], can inhibit the activation of HSCs and reduce liver fibrosis. These drugs benefit patients with alcoholic liver disease and NASH.

HSCs are also involved in hepatic angiogenesis and hepatic sinus vascular remodeling. When stimulated by inflammatory factors or hypoxia, HSCs can directly express VEGF and angiopoietin-1, influencing angiogenesis in the liver [40,41]. Pathological angiogenesis is related to the process of liver fibrosis and cirrhosis [42]. During liver fibrosis, fibrous scar tissue presses against the portal vein and central vein, leading to increased intrahepatic resistance. Simultaneously, liver sinus capillarization and fibrous scar obstruction also increase the resistance of blood flow and oxygen diffusion. These processes result in low oxygen conditions in the liver and gene expression, which are sensitive to oxygen concentration such as hypoxia-inducible factors (HIFs). Pathological angiogenesis cannot improve the oxygen level in the liver because of the high permeability of new blood vessels induced by VEGF. Therefore, pathologic angiogenesis and hypoxemia interfere with normal tissue repair and promote the development of liver fibrosis [43]. Pathological angiogenesis plays an important role in liver fibrosis and thus has been considered as an important therapeutic target for the reversal of liver fibrosis. One study found that the knockout of HIF-1α in rats significantly ameliorated liver fibrosis, indicating that improving intrahepatic hypoxia could effectively treat such a disease [44].
