School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
Int J Mol Sci. 2023 Feb 8;24(4):3415. doi: 10.3390/ijms24043415.
Liver fibrosis is a pathological process characterized by the excessive synthesis and accumulation of extracellular matrix proteins (ECMs) contributed mainly by the activated hepatic stellate cells (HSCs). Currently, no direct and effective anti-fibrotic agents have been approved for clinical use worldwide. Although the dysregulation of Eph receptor tyrosine kinase EphB2 has been reported to associate with the development of liver fibrosis, the involvement of other Eph family members in liver fibrosis remains underexplored. In this study, we found that the expression of EphB1 is significantly increased accompanying remarkable neddylation in activated HSCs. Mechanistically, this neddylation enhanced the kinase activity of EphB1 by the prevention of its degradation, thereby promoting the proliferation, migration, and activation of HSCs. Our findings revealed the involvement of EphB1 in the development of liver fibrosis through its neddylation, which provides new insights into the Eph receptor signaling and a potential target for the treatment of liver fibrosis.
肝纤维化是一种病理过程，其特征是细胞外基质蛋白（ECMs）的过度合成和积累，主要由活化的肝星状细胞（HSCs）贡献。目前，全球尚未批准任何直接有效的抗纤维化药物用于临床。尽管 Eph 受体酪氨酸激酶 EphB2 的失调已被报道与肝纤维化的发展有关，但 Eph 家族其他成员在肝纤维化中的参与仍未得到充分探索。在这项研究中，我们发现 EphB1 的表达显著增加，同时活化的 HSCs 中出现显著的类泛素化。在机制上，这种类泛素化通过阻止 EphB1 的降解来增强其激酶活性，从而促进 HSCs 的增殖、迁移和激活。我们的研究结果揭示了 EphB1 通过其类泛素化参与肝纤维化的发展，为 Eph 受体信号提供了新的见解，并为肝纤维化的治疗提供了一个潜在的靶点。
