Galicia-Moreno Marina, Lucano-Landeros Silvia, Monroy-Ramirez Hugo Christian, Silva-Gomez Jorge, Gutierrez-Cuevas Jorge, Santos Arturo, Armendariz-Borunda Juan
Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico.
Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45201, Jalisco, Mexico.
Antioxidants (Basel). 2020 Oct 13;9(10):980. doi: 10.3390/antiox9100980.
Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.
肝脏疾病是一个严重的健康问题，每年在全球导致200万人死亡，主要原因是肝硬化及其并发症。氧化应激在肝脏疾病的发展中起着重要作用。为了维持适当的内环境稳态，自由基和抗氧化介质之间必须保持平衡。核因子红细胞2相关因子（Nrf2）及其负调节因子 Kelch样ECH相关蛋白1（Keap1）构成了一种对抗氧化应激损伤的防御机制，越来越多的证据认为该信号通路是治疗肝脏疾病的关键药理学靶点。在这篇综述中，我们提供了关于Nrf2及其在主要肝脏疾病（如酒精性肝损伤、病毒性肝炎、脂肪变性、脂肪性肝炎、胆汁淤积性损伤和肝癌）发展中所起作用的详细且最新的证据。阐述了Nrf2细胞信号传导的分子和细胞机制，以及关键且相关的抗氧化药物，并描述了Keap1/Nrf2调节如何积极影响治疗反应的机制。最后，概述了关于表观遗传修饰及其与Keap1/Nrf2信号调节联系的近期令人兴奋的发现。
