*4.1. NPs as Therapeutic Agents*

Owing to their distinctive bioactive properties, inorganic NPs alone can be used as therapeutic agents for liver fibrosis therapy [60–62]. Both titanium dioxide NPs (TiO2 NPs) and silicon dioxide NPs (SiO2 NPs) can inhibit the expression of collagen I and α-SMA. They also facilitate collagen I degradation by upregulating matrix metalloproteinases (MMPs) and downregulating tissue inhibitors of metalloproteinases (TIMPs), indicating the potential antifibrotic activities of TiO2 NPs and SiO2 NPs in vitro [63]. These NPs further exhibit anti-adhesive and anti-migratory effects by regulating epithelial−mesenchymal transition (EMT) gene expression and revert TGF-β-activated HSCs to a quiescent state (Figure 3). Owing to their anti-inflammatory properties, cerium oxide NPs reduce liver steatosis, portal hypertension, and liver fibrosis in rats [64]. Oral exposure of citrate-functionalized Mn3O4 NPs can protect the liver from carbon tetrachloride (CCl4)-induced cirrhosis, fibrosis, and oxidative stress because of the increased antioxidant properties of Mn3O4 NPs upon acid treatment in the stomach [65]. ZnO NPs also ameliorate liver fibrosis by reducing lipid peroxidation, oxidative stress, and inflammation in dimethylnitrosamine-induced liver damage [66].

**Figure 3.** Model for TiO2 NPs and SiO2 NPs ameliorated fibrosis, adhesion and migration of HSCs. TiO2 NPs and SiO2 NPs can suppress the expression of α-SMA and deposition of Col-I induced by TGF-β. ECM was degraded by upregulating MMP-13 and downregulating TIMP-1. Therefore, adhesion of LX-2 cells was reduced. Furthermore, NPs stimulated the expression of E-Cad and reduced the expression of N-Cad, and, therefore, aggravated the migratory phenotype. Reproduced with permission from [63]. Copyright American Chemical Society, 2018.

In addition to metal oxide NPs, other types of inorganic NPs are also used to treat liver fibrosis. A study found that gold NPs reduced liver fibrosis in a rat model of ethanol- and methamphetamineinduced liver injury by inhibiting the activity of Kupffer cells and HSCs [67]. The mechanism involves the regulation of AKT/PI3K and MAPK signaling pathways by gold NPs, thereby reducing pro-inflammatory cytokine secretion and oxidative stress. Another study reported that vitamin E-modified selenium NPs can attenuate liver fibrosis by reducing oxidative stress [68].
