Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, China; NHC Key Laboratory of Organ Transplantation, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
Chem Biol Interact. 2022 Feb 25;354:109839. doi: 10.1016/j.cbi.2022.109839. Epub 2022 Jan 31.
Liver fibrosis is the result of most chronic inflammatory liver damage and seriously endangers human health. However, no drugs have been approved to treat this disease. Previous studies showed that the Toll-like receptors (TLRs)/myeloid differentiation factor-88 (MyD88)/nuclear factor-κB (NF-κB) pathway plays a key role in liver fibrosis. TJ-M2010-5 is a self-developed small molecule MyD88 inhibitor, which has been proven to have a good protective effect in a variety of inflammatory disease models. In the present study, to investigate the anti-fibrotic effect of TJ-M2010-5, mice were injected with carbon tetrachloride (CCl) in vivo and LX2 cells (a human hepatic stellate cell line) were treated with TGF-β1 in vitro to induce liver fibrosis. In vivo studies showed that TJ-M2010-5 attenuated the CCl-induced liver damage, collagen accumulation, and the activation of hepatic stellate cells by inhibiting the nuclear transfer of NF-κB. Moreover, in vitro experiments of LX2 cells stimulated with TGF-β1 further indicated that the NF-κB pathway is involved in the development of liver fibrosis. TJ-M2010-5 significantly inhibited the proliferation and activation of LX2 cells. In addition, TJ-M2010-5 upregulated the expression of bone morphogenetic protein and membrane-bound inhibitor (BAMBI) in LX2 cells by blocking the activation of MyD88/NF-κB, thereby inhibiting the phosphorylation of Smad2/3 and the expression of collagen I (COL1A1) induced by TGF-β1. In conclusion, this study illustrates the anti-hepatic fibrosis effect of TJ-M2010-5 and provides a new treatment method for liver fibrosis.
肝纤维化是大多数慢性炎症性肝损伤的结果，严重危害人类健康。然而，目前尚无药物被批准用于治疗这种疾病。先前的研究表明，Toll 样受体（TLRs）/髓样分化因子 88（MyD88）/核因子-κB（NF-κB）途径在肝纤维化中起关键作用。TJ-M2010-5 是一种自主研发的小分子 MyD88 抑制剂，已被证明在多种炎症性疾病模型中具有良好的保护作用。在本研究中，为了研究 TJ-M2010-5 的抗纤维化作用，我们在体内用四氯化碳（CCl）注射小鼠，并在体外用 TGF-β1 处理 LX2 细胞（人肝星状细胞系）诱导肝纤维化。体内研究表明，TJ-M2010-5 通过抑制 NF-κB 的核转位，减轻 CCl 诱导的肝损伤、胶原积累和肝星状细胞的激活。此外，用 TGF-β1 刺激的 LX2 细胞的体外实验进一步表明，NF-κB 途径参与了肝纤维化的发展。TJ-M2010-5 显著抑制 LX2 细胞的增殖和激活。此外，TJ-M2010-5 通过阻断 MyD88/NF-κB 的激活，上调 LX2 细胞中骨形态发生蛋白和膜结合抑制剂（BAMBI）的表达，从而抑制 TGF-β1 诱导的 Smad2/3 磷酸化和胶原 I（COL1A1）的表达。总之，本研究阐明了 TJ-M2010-5 的抗肝纤维化作用，为肝纤维化提供了一种新的治疗方法。
