NOX as a Therapeutic Target in Liver Disease

Abstract

The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease’s progression.

Pharmacological inhibition of p300 ameliorates steatosis, inflammation, and fibrosis in mice with non-alcoholic steatohepatitis

“…Interestingly, p300 inhibition reduced NOX4 and ACSL4 expression, while enhancing GPX4 expression. NOX4 represents a major enzyme responsible for reactive oxygen species (ROS) production in the liver [ 40 ], and recent studies have highlighted the role of NOX4-mediated ROS production in promoting lipid peroxidation in ferroptosis [ 41 , 42 ]. Bettaieb et al demonstrated that hepatic NOX4 expression is upregulated in animal models of NASH and in NASH patients [ 43 ].…”

6-Shogaol Ameliorates Liver Inflammation and Fibrosis in Mice on a Methionine- and Choline-Deficient Diet by Inhibiting Oxidative Stress, Cell Death, and Endoplasmic Reticulum Stress

“…Furthermore, our study unveiled that the MCD diet triggered the upregulation of NOX4 and HO-1 in mice. While NOX4, a pro-oxidant enzyme, contributes to ROS generation in various pathological processes [ 41 , 42 ], HO-1 operates as an antioxidant enzyme, safeguarding against oxidative damage and bolstering cellular resilience [ 43 , 44 ]. Therefore, the elevated expression of HO-1 in response to the MCD diet seems to represent a defensive reaction against oxidative damage.…”

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

“…Setanaxib (GKT137831) is a dual Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1/4 inhibitor, which exerts anti-inflammatory and antifibrotic effects. GKT137831 attenuated liver fibrosis, decreased hepatocyte apoptosis and reactive species of oxygen production in animal models ( 170 ). GKT137831 improved markers of cholestasis and inflammation in PBC.…”