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Abstract：
Activation of hepatic stellate cells (HSCs) is critical in the progression of liver fibrosis and is a promising target for anti-hepatic fibrosis drug development. Moreover, effective pharmacological interventions targeting this pathomechanism are scarce. Our study confirms the therapeutic value of β-sitosterol, a major constituent of Ranunculus ternatus Thunb, in hepatic fibrosis and identifies its underlying mechanisms. After treatment with β-sitosterol, CCL4-induced hepatic fibrosis was reversed in mice, while inflammatory and hepatic fibrosis indices were improved. Meanwhile, we explored the molecular mechanism of β-sitosterol treatment for hepatic fibrosis and, based on RNA-seq results, found that the ameliorative effect of β-sitosterol on hepatic fibrosis was associated with the MK3 and NF-κB signalling pathways. MK3, an important kinase in the MAPK pathway, plays a role in transmitting upstream and downstream signals, whereas the NF-κB signalling pathway has been shown to be associated with HSC activation. We verified the interaction between MK3 and IκB in HSC cells using endogenous Co-IP, whereas β-sitosterol reduced the binding of MK3 to IκB and the activation of the NF-κB signalling pathway. Our findings reveal the mechanism of β-sitosterol in the treatment of liver fibrosis, suggesting that β-sitosterol may be a promising drug for the treatment of liver fibrosis and deserves further investigation.
摘要：
肝星状细胞（HSC）的激活在肝纤维化的进展中是关键的，并且是抗肝纤维化药物开发的有希望的靶标。此外，针对这种病理机制的有效药物干预措施很少。我们的研究证实了β-谷甾醇的治疗价值，毛茸茸的主要成分，在肝纤维化，并确定其潜在的机制。用β-谷甾醇治疗后，CCL4诱导的肝纤维化在小鼠中被逆转，而炎症和肝纤维化指标得到改善。同时,探讨β-谷甾醇治疗肝纤维化的分子机制,基于RNA-SEQ结果，发现β-谷甾醇对肝纤维化的改善作用与MK3和NF-κB信号通路有关。MK3是MAPK通路中的重要激酶,在传输上行和下行信号中发挥作用，而NF-κB信号通路已被证明与HSC激活有关。我们使用内源性Co-IP验证了HSC细胞中MK3和IκB之间的相互作用，而β-谷甾醇降低了MK3与IκB的结合以及NF-κB信号通路的激活。我们的发现揭示了β-谷甾醇治疗肝纤维化的机制，提示β-谷甾醇可能是治疗肝纤维化的有希望的药物，值得进一步研究。
