School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Int J Mol Sci. 2022 Oct 20;23(20):12572. doi: 10.3390/ijms232012572.
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.
肝纤维化是由反复和持续的肝损伤引起的。它可以从肝细胞损伤开始，发展为炎症，炎症招募并激活额外的肝脏免疫细胞，导致肝星状细胞（HSCs）的激活。HSCs 是肌成纤维细胞（MFs）的主要来源，导致胶原合成和细胞外基质蛋白积累。尽管没有获得 FDA 和 EMA 批准的抗纤维化药物，但抗病毒治疗在预防甚至逆转肝纤维化进展方面取得了显著进展，但对于病毒、酒精或非酒精性脂肪性肝病、遗传或自身免疫性肝病患者，这种策略仍然难以实现。由于病因的复杂性，可能需要影响两个或多个靶点的联合治疗。在这里，我们回顾了肝纤维化的发病机制和涉及的信号通路，以及肝纤维化治疗的各种分子靶点。还总结了针对肝纤维化治疗中不同细胞的有效药物递送系统的开发。我们重点介绍了临床试验和临床前测试中有前途的抗纤维化事件，包括小分子和天然化合物。最后，我们讨论了开发抗纤维化疗法的挑战和机遇。
