Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function


Oxidative stress plays a crucial role in the development of alcoholic liver disease (ALD), however effective pharmacological treatment for oxidative injury is still lacking. The objective of this study was to determine whether inhibition of NADPH oxidase activity could reverse alcohol-induced liver injury via protecting mitochondrial functions.


C57BL/6J mice were pair-fed with Lieber-DeCarli control or ethanol diet for four week with or without administration with 30mg/kg/d GKT137831, a NOX4 inhibitor for the last two weeks. H4IIEC3 cells were transfected with scrambled or NOX4 shRNA. Cells were then treated with 200mM ethanol for 48h.


Alcohol exposure induced NOX4 expression in the liver and mitochondrial fraction. GKT137831 partially reversed alcohol-induced liver injury and elevation of serum H2O2. The levels of mitochondrial ROS, mitochondrial DNA, respiratory chain complex IV, and hepatic ATP were partially reversed by GKT137831 after alcohol exposure. Furthermore GKT137831 ameliorated alcohol-induced lipid accumulation and increased HNF-4α and β-oxidation enzymes. GKT137831 also decreased alcohol-induced apoptosis coupled with decreased insertion of Bax into mitochondria and decreased activation of cleaved caspase-9 and cleaved PARP. Mechanistic study shows that ethanol induced expression of NOX4 in H4IIEC3 cells. Knockdown of NOX4 caused an increased mitochondrial membrane potential, decreased mitochondrial superoxide levels, reduced number of apoptotic cells, decreased lipid accumulation, and improved ATP levels and NAD+/NADH ratio after ethanol treatment.


Pharmacological inhibition of NOX4 activity protects against alcohol-induced fat accumulation and activation of intrinsic apoptosis via improving mitochondrial function.

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S7171 Setanaxib (GKT137831) Setanaxib (GKT137831, GKT831) is a potent, dual NADPH oxidase NOX1/NOX4 inhibitor with Ki of 110 nM and 140 nM, respectively. Treatment with GKT137831 suppresses reactive oxygen species (ROS) production. GKT137831 partly inhibits ferroptosis. (41) (4)

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