Schisantherin A ameliorates liver fibrosis through TGF-β1mediated activation of TAK1/MAPK and NF-κB pathways in vitro and in vivo

Backgroud: Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role.

Purpose: The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism.

Methods: The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-β1 (TGF-β1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-β-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA.

Results: SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-β1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-β1 and then the expression of MAPK and NF-κB signaling pathway-related proteins.

Conclusion: Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-β1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-β1 mediated TAK1/MAPK and signal pathways.