OBJECTIVE To evaluate the anti-hepatic fibrosis effect of the fungal-derived compound MCA17-1 and to explore its possible mechanism of action.

METHODS TGF-β1-induced liver fibrosis model in LX-2 cells and CCl₄-induced liver fibrosis model in mice were used to evaluate the antifibrotic effect of MCA17-1. The transcript levels and protein expression of α-SMA, COL1A1, and Fibronectin 1 were detected in LX-2 cells and mouse livers using q-PCR and Western blotting. Cell scratch assay was performed to evaluate the effect of MCA17-1 on the migration of HSCs.Serum biochemical indexes, H&E staining, Masson staining, Sirius red staining as well as immunohistochemistry were used to evaluate the anti-hepatic fibrosis effect of MCA17-1 in vivo. Western blotting assay was used to detect the changes of TGF-β1, Smad 2/3, p-Smad 2 and p-Smad 2/3 protein expression in LX-2 cells and mouse liver tissues.

RESULTS  Compared with the TGF-β1 model group, both 1 μmol·L⁻¹ and 5 μmol·L⁻¹ doses of MCA17-1 significantly decreased the transcript levels and protein expression of α-SMA, COL1A1, and Fibronectin 1(P<0.001) and impaired the migration ability of LX-2 cells(P<0.05). Compared with the CCl₄ model group, both 2.5 mg·kg⁻¹ and 5 mg·kg⁻¹ doses of MCA17-1 significantly decreased the mRNA levels of α-SMA, COL1A1, and Fibronectin 1, as well as the protein expression of α-SMA and COL1A1 in mouse liver tissues(P<0.01). Compared with the CCl₄ model group, both low-dose and high-dose MCA17-1 significantly reduced serum ALT and AST levels(P<0.05), ameliorated CCl₄-induced histopathological changes in the liver, decreased collagen fiber deposition(P<0.01), and suppressed the phosphorylation levels of Smad2/3 proteins in both TGF-β1- and CCl₄-induced liver fibrosis models(P<0.05). Additionally, MCA17-1 reduced TGF-β1 protein expression in the cellular model of liver fibrosis(P<0.001).

CONCLUSION  MCA17-1 inhibited TGF-β1-induce HSCs activation in vitro, ameliorated CCl₄-induced hepatic injury, and attenuated hepatic fibrosis in mice. This effect may be related to its specific inhibition of the TGF-β1/Smad signaling pathway, suggesting that MCA17-1, a novel fungal-derived compound, may serve as a potential therapeutic candidate for the treatment of liver fibrosis.