Abstract
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.
Highlights
In light of these considerations, this review aims at summarizing the current knowledge about oxidative stress involvement in the Non-alcoholic fatty liver disease (NAFLD)–non-alcoholic steatohepatitis (NASH)–hepatocellular carcinoma (HCC)
Epidemiological data clearly indicate that NAFLD/NASH causes a dramatic increase in the prevalence of HCC development [31], being NASH the etiological cause of HCC, in the prevalence of HCC development [31], being NASH the etiological cause of HCC, which develops most rapidly among patients who are in a list for liver transplantation in which develops most rapidly among patients who are in a list for liver transplantation in the USA [32]
The role of NADPH oxidases (NOXs) in the progression and worsening of fatty liver disease, either complicated or not by inflammation, and its transition to liver cancer have been outlined by both preclinical mechanistic studies and clinical observations
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Numerous studies described the specific mechanisms of the NASH–HCC transition, unraveling that metabolic and oxidative stress, immune and endocrine alterations, and pathological inflammatory responses are fundamental players in this process [6]. In light of these considerations, this review aims at summarizing the current knowledge about oxidative stress involvement in the NAFLD–NASH–HCC transition, focusing on the role of the enzymes NADPH oxidases (NOXs)
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