Zhou Jiaming, Zheng Qiuxian, Chen Zhi
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Cell Dev Biol. 2022 Feb 10;10:826204. doi: 10.3389/fcell.2022.826204. eCollection 2022.
Oxidative stress is the leading cause of most liver diseases, such as drug-induced liver injury, viral hepatitis, and alcoholic hepatitis caused by drugs, viruses, and ethanol. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (Keap1-Nrf2) system is a critical defense mechanism of cells and organisms in response to oxidative stress. Accelerating studies have clarified that the Keap1-Nrf2 axis are involved in the prevention and attenuation of liver injury. Nrf2 up-regulation could alleviate drug-induced liver injury in mice. Moreover, many natural Nrf2 activators can regulate lipid metabolism and oxidative stress of liver cells to alleviate fatty liver disease in mice. In virus hepatitis, the increased Nrf2 can inhibit hepatitis C viral replication by up-regulating hemeoxygenase-1. In autoimmune liver diseases, the increased Nrf2 is essential for mice to resist liver injury. In liver cirrhosis, the enhanced Nrf2 reduces the activation of hepatic stellate cells by reducing reactive oxygen species levels to prevent liver fibrosis. Nrf2 plays a dual function in liver cancer progression. At present, a Nrf2 agonist has received clinical approval. Therefore, activating the Nrf2 pathway to induce the expression of cytoprotective genes is a potential option for treating liver diseases. In this review, we comprehensively summarized the relationships between oxidative stress and liver injury, and the critical role of the Nrf2 pathway in multiple liver diseases.
氧化应激是大多数肝脏疾病的主要原因，如药物性肝损伤、病毒性肝炎以及由药物、病毒和乙醇引起的酒精性肝炎。 Kelch样ECH相关蛋白1-核因子E2相关因子2（Keap1-Nrf2）系统是细胞和生物体应对氧化应激的关键防御机制。越来越多的研究表明，Keap1-Nrf2轴参与肝脏损伤的预防和减轻。上调Nrf2可减轻小鼠药物性肝损伤。此外，许多天然的Nrf2激活剂可调节肝细胞的脂质代谢和氧化应激，以减轻小鼠脂肪肝疾病。在病毒性肝炎中，Nrf2增加可通过上调血红素加氧酶-1抑制丙型肝炎病毒复制。在自身免疫性肝病中，Nrf2增加对小鼠抵抗肝损伤至关重要。在肝硬化中，增强的Nrf2通过降低活性氧水平减少肝星状细胞的激活，以预防肝纤维化。Nrf2在肝癌进展中发挥双重作用。目前，一种Nrf2激动剂已获得临床批准。因此，激活Nrf2途径以诱导细胞保护基因的表达是治疗肝脏疾病的潜在选择。在本综述中，我们全面总结了氧化应激与肝损伤之间的关系，以及Nrf2途径在多种肝脏疾病中的关键作用。
