Huang Zheng, Nie Shangshu, Wang Shuhui, Wang Han, Gong Jin, Yan Wei, Tian Dean, Liu Mei
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
Pharmaceuticals (Basel). 2023 Feb 17;16(2):316. doi: 10.3390/ph16020316.
Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein-protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases.
由于现有治疗药物的局限性，自身免疫性肝炎（AIH）的新型治疗方法备受需求。木香内酯因其抗炎和肝保护功能而成为有前景的候选药物，但其在AIH中的作用仍不清楚。在本研究中，我们整合网络药理学和实验验证以揭示木香内酯在AIH中的作用及机制。从数据库中获得了木香内酯和AIH的总共73个共同靶点。通路富集分析表明PI3K-AKT通路是木香内酯在AIH中的核心通路。蛋白质-蛋白质相互作用网络分析和分子对接显示SRC和IGF1R可能起关键作用。在两种小鼠AIH模型中，木香内酯显著减轻了肝损伤、炎症和纤维化，这通过肝脏大体外观、血清转氨酶、坏死面积、脾脏指数、免疫细胞浸润和胶原沉积得以体现。蛋白质印迹法和免疫组织化学证实，AIH模型中磷酸化的AKT、SRC和IGF1R上调，而给予木香内酯可抑制这些蛋白质的磷酸化。总之，木香内酯显著改善小鼠AIH。其治疗作用可能通过抑制PI3K-AKT通路的激活以及抑制SRC和IGF1R的磷酸化来实现。我们的研究首次揭示了木香内酯在AIH中的强效治疗作用以及SRC和IGF1R在AIH中的潜在作用，这可能进一步有助于AIH和其他自身免疫性疾病的新药研发。
