Alleviation of Hepatic Steatosis by 4‐azidophlorizin via the Degradation of Geranylgeranyl Diphosphate Synthase by the Ubiquitin‐Proteasome Pathway in Vivo and in Vitro

Abstract There are no known approved pharmacotherapies for non‐alcoholic fatty liver disease (NAFLD) in the clinical setting. Although studies have provided substantial evidence that geranylgeranyl diphosphate synthase (GGPPS) is a potential therapeutic target for the treatment of NAFLD corresponding drug screening is rare. A GGPPS‐targeted inhibitor is identified using a structure‐based virtual small molecule screening method. The interaction of 4‐AZ and GGPPS is detected by microscale thermophoresis. 4‐AZ degradation of GGPPS by the ubiquitin‐proteasome pathway is detected by western blotting. The anti‐steatotic effect of 4‐AZ in vivo is detected by CT. Lipid‐related gene detection is detected by real‐time PCR both in primary hepatocytes and mice. The compound inhibits the accumulation of lipids in primary hepatocytes and decreases lipogenic gene expression through GGPPS. Pharmacological studies show that 4‐AZ can attenuate hepatic steatosis and improve liver injury in high‐fat diet‐induced mice. This data provides a novel application of 4‐AZ NAFLD therapy, proving that the inhibition of GGPPS is a novel strategy for the treatment of NAFLD.