Han Jin, Wu Jun, Kou Wen-Tao, Xie Li-Na, Tang Ya-Li, Zhi Da-Long, Li Ping, Chen Dan-Qian
Northwest University Chang An Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China.
Department of Nephrology, Chang An District Hospital, Xi'an, Shaanxi, China.
Front Pharmacol. 2024 Dec 4;15:1476699. doi: 10.3389/fphar.2024.1476699. eCollection 2024.
Fibrosis is the outcome of any abnormal tissue repair process that results in normal tissue replacement with scar tissue, leading to persistent tissue damage and cellular injury. During the process of fibrosis, many cytokines and chemokines are involved, and their activities are controlled by post-translational modifications, especially SUMOylation and NEDDylation. Both these modifications entail a three-step process of activation, conjugation, and ligation that involves three kinds of enzymes, namely, E1 activating, E2 conjugating, and E3 ligase enzymes. SUMOylation participates in organ fibrosis by modulating FXR, PML, TGF-β receptor I, Sirt3, HIF-1α, and Sirt1, while NEDDylation influences organ fibrosis by regulating cullin3, NIK, SRSF3, and UBE2M. Further investigations exhibit the therapeutic potentials of SUMOylation/NEDDylation activators and inhibitors against organ fibrosis, especially ginkgolic acid in SUMOylation and MLN4924 in NEDDylation. These results demonstrate the therapeutic effects of SUMOylation and NEDDylation against organ fibrosis and highlight their activators as well as inhibitors as potential candidates. In the future, deeper investigations of SUMOylation and NEDDylation are needed to identify novel substrates against organ fibrosis; moreover, clinical investigations are needed to determine the therapeutic effects of their activators and inhibitors that can benefit patients. This review highlights that SUMOylation and NEDDylation function as potential therapeutic targets for organ fibrosis.
纤维化是任何异常组织修复过程的结果，该过程导致正常组织被瘢痕组织替代，从而导致持续性组织损伤和细胞损伤。在纤维化过程中，许多细胞因子和趋化因子都参与其中，并且它们的活性受翻译后修饰的控制，尤其是小泛素样修饰和NEDD化修饰。这两种修饰都需要经过激活、缀合和连接的三步过程，涉及三种酶，即E1激活酶、E2缀合酶和E3连接酶。小泛素样修饰通过调节法尼醇X受体（FXR）、早幼粒细胞白血病蛋白（PML）、转化生长因子-β受体I（TGF-β receptor I）、沉默调节蛋白3（Sirt3）、缺氧诱导因子-1α（HIF-1α）和沉默调节蛋白1（Sirt1）参与器官纤维化，而NEDD化修饰通过调节cullin3、NF-κB诱导激酶（NIK）、丝氨酸/精氨酸丰富剪接因子3（SRSF3）和泛素结合酶E2M（UBE2M）影响器官纤维化。进一步的研究显示了小泛素样修饰/NEDD化修饰激活剂和抑制剂对器官纤维化的治疗潜力，特别是小泛素样修饰中的银杏酸和NEDD化修饰中的MLN4924。这些结果证明了小泛素样修饰和NEDD化修饰对器官纤维化的治疗作用，并突出了它们的激活剂和抑制剂作为潜在候选药物的地位。未来，需要对小泛素样修饰和NEDD化修饰进行更深入的研究，以确定针对器官纤维化的新底物；此外，还需要进行临床研究，以确定其激活剂和抑制剂对患者有益的治疗效果。本综述强调，小泛素样修饰和NEDD化修饰作为器官纤维化的潜在治疗靶点发挥作用。
