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.

中文翻译：

---

体内和体外 4-叠氮基苷通过泛素-蛋白酶体途径降解香叶基香叶基二磷酸合酶减轻肝脏脂肪变性

临床上尚无已知的批准的治疗非酒精性脂肪肝病（NAFLD）的药物疗法。尽管研究提供了大量证据表明香叶基香叶基二磷酸合酶（GGPPS）是治疗NAFLD的潜在治疗靶点，但相应的药物筛选却很少。使用基于结构的虚拟小分子筛选方法鉴定了 GGPPS 靶向抑制剂。通过微尺度热泳检测 4-AZ 和 GGPPS 的相互作用。通过蛋白质印迹法检测泛素-蛋白酶体途径对 GGPPS 的 4-AZ 降解。通过CT检测4-AZ体内的抗脂肪变性作用。通过实时 PCR 检测原代肝细胞和小鼠中的脂质相关基因。该化合物抑制原代肝细胞中脂质的积累，并通过 GGPPS 降低脂肪生成基因的表达。药理学研究表明，4-AZ可以减轻高脂饮食诱导的小鼠肝脏脂肪变性并改善肝损伤。该数据提供了4-AZ NAFLD治疗的新应用，证明抑制GGPPS是治疗NAFLD的新策略。