Gabbia Daniela, Cannella Luana, De Martin Sara
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
Biomedicines. 2021 Jun 17;9(6):687. doi: 10.3390/biomedicines9060687.
A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.
众多实验和临床研究支持氧化应激在非酒精性脂肪性肝病（NAFLD）及其向炎症性并发症非酒精性脂肪性肝炎（NASH）的转变，以及在其向肝细胞癌（HCC）的威胁性演变中所起的特殊作用。NADPH氧化酶（NOXs）是产生活性氧（ROS）的酶，其在肝细胞中的丰度与炎症和免疫反应密切相关。在此，我们回顾了关于该主题的最新发现，重点关注NOXs在脂肪性肝病不同阶段的作用，并描述了目前关于其作用机制的知识。我们得出结论，尽管人们一致认为，由于NOX产生的ROS在维持NAFLD向NASH转变的炎症恶性循环中起作用，其在非肿瘤性疾病中具有毒性，但其在向HCC的肿瘤性转变中的作用存在争议。在这方面，有迹象表明NOX亚型存在差异效应，因为NOX1和NOX2起有害作用，而在一些研究中，NOX4表达增加似乎与更好的HCC预后相关。需要进一步研究以全面阐明NOXs的作用机制及其与调节脂肪变性和肝癌发展的信号通路的关系。
