AIM: To investigate the role of Gadd45 a in hepatic fibrosis and the transforming growth factor(TGF)-β/Smad signaling pathway.METHODS: Wild-type male BALB/c mice were treated with CCl_4 to induce a model of chronic liver injury. Hepatic stellate cells(HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs(si RNAs) targeting Gadd45 a or the pc DNA3.1-Gadd45 a recombinant plasmid. Cellular α-smooth muscle actin(α-SMA), β-actin, type Ⅰ collagen, phosphoSmad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The m RNA levels of α-SMA, β-actin, and type Ⅰ collagen were determined by quantitative real-time(q RT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate.Gadd45a, Gadd45 b, anti-Gadd45 g, type Ⅰ collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses. RESULTS: Significant downregulation of Gadd45 a, but not Gadd45 b or Gadd45 g, accompanied by activation of the TGF-β/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl_4 treatment. Overexpression of Gadd45 a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient knockdown of Gadd45 a with si RNA reversed this process. Gadd45 a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and(CAGA)_9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45 a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes.CONCLUSION: Gadd45 a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β/Smad signaling. AIM: To investigate the role of Gadd45 a in hepatic fibrosis and the transforming growth factor (TGF) -β / Smad signaling pathway. METHODS: Wild-type male BALB / c mice were treated with CCl_4 to induce a model of chronic liver injury. (HSCs) were isolated from the liver of BALB / c mice and were treated with small interfering RNAs (si RNAs) targeting Gadd45 a or the pc DNA3.1-Gadd45 a recombinant plasmid. Cellular α-smooth muscle actin (α -SMA), β-actin, type I collagen, phosphoSmad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots quantitative real-time (q RT) -PC analyzes. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45 g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyzes. RESULTS: Significant downregul ation of Gadd45 a, but not Gadd45 b or Gadd 45 g, accompanied by activation of the TGF-β / Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl_4 treatment. Overexpression of Gadd 45 a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient transfection of Gadd45 a with si RNA-reversed-directed process. Gadd45 a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA) _9 MLP-Luc, an artificialadd3 / 4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45 a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes. CONCLUSION: Gadd45 a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β / Smad signaling.