State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety; Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450007, China.
Department of Pathology, Oslo University Hospital, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.
Biochem Cell Biol. 2022 Aug 1;100(4):309-324. doi: 10.1139/bcb-2021-0585. Epub 2022 May 11.
Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of ∼20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1-UBC12 interaction inhibitor HZX-960 was discovered with an IC value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor β-induced liver fibrotic responses by reducing the deposition of collagen I and α-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment.
肝纤维化是一种非常常见的健康问题，目前缺乏有效的治疗方法。Cullin RING E3 连接酶 (CRLs) 调节哺乳动物细胞中约 20%的蛋白质的周转率。Neddylation 是通过连续的酶促反应将 NEDD8 共价连接到 Cullin 蛋白的过程，对于 CRLs 的激活至关重要，最近发现在肝纤维化中升高。NEDD8-激活酶 E1 特异性抑制导致肝损伤减少，其特征为凋亡、炎症和纤维化减少。然而，DCN1 作为一种共 E3 连接酶在肝纤维化中的相关性尚不清楚。在这里，发现了一种新型有效的 DCN1-UBC12 相互作用抑制剂 HZX-960，其 IC 值为 9.37 nmol/L，可抑制 Cullin3 的 Neddylation。重要的是，我们发现 HZX-960 治疗可以通过减少胶原 I 和α-平滑肌肌动蛋白的沉积，以及上调细胞 NF-E2 相关因子 2、血红素加氧酶 1 和 NADPH 醌氧化还原酶-1 水平，来减轻转化生长因子 β 诱导的肝纤维化反应。此外，在 CCl 诱导的小鼠肝组织中发现 DCN1 上调，并且 HZX-960 降低了小鼠肝纤维化信号。因此，我们的数据表明 HZX-960 具有抗肝纤维化能力，并且 DCN1 可能是肝纤维化治疗的潜在治疗靶点。
