College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea.
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea.
Biochem Pharmacol. 2021 Nov;193:114764. doi: 10.1016/j.bcp.2021.114764. Epub 2021 Sep 13.
Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. In this review, we present the function of ubiquitination and latest findings on diverse mechanism of PTMs, UPS and autophagy which significantly contribute to the pathogenesis of alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cirrhosis, and HCC. Despite its high prevalence, morbidity, and mortality, there are only few FDA approved drugs that could be administered to CLD patients. The goal of this review is to present a variety of pathways and therapeutic targets involving ubiquitination in the pathogenesis of CLD. Further, this review summarizes collective views of pharmaceutical inhibition or activation of recent drugs targeting UPS and autophagy system to highlight potential targets and new approaches to treat CLD.
慢性肝病（CLD）被认为是全球死亡的主要原因。在西方国家，酒精摄入量增加和高糖高脂肪食物的过度摄入促进了 CLD 的进展，如酒精性肝病（ALD）和非酒精性肝病（NAFLD）。越来越多的证据和研究表明，泛素是一种 75 个氨基酸的蛋白质，通过动态翻译后修饰（PTMs）在 CLD 的发病机制中发挥关键作用，这些 PTMs 可产生多种细胞后果，如通过泛素-蛋白酶体系统（UPS）和自噬进行蛋白降解，以及调节信号转导。在这篇综述中，我们介绍了泛素化的功能以及最新发现的各种 PTMs、UPS 和自噬机制，这些机制对酒精性肝病（ALD）、非酒精性脂肪性肝病（NAFLD）、肝硬化和 HCC 的发病机制有重要贡献。尽管 CLD 的发病率、发病率和死亡率很高，但只有少数几种获得 FDA 批准的药物可用于 CLD 患者。本综述的目的是介绍涉及 CLD 发病机制的泛素化的各种途径和治疗靶点。此外，本综述总结了靶向 UPS 和自噬系统的近期药物的抑制或激活的综合观点，以突出治疗 CLD 的潜在靶点和新方法。
