7-aminocephalosporanic acid, a novel HSP90β inhibitor, attenuates HFD-induced hepatic steatosis

Hepatic steatosis is one of the most important causes of liver disease worldwide. Heat shock protein 90 (HSP90) is essential for numerous client proteins. Recently, more attention was focused on increased HSP90 levels in hepatic steatosis, especially HSP90 beta. Thus, great efforts have been made to develop HSP90 beta inhibitors, and most natural inhibitors are derived from microorganisms. In this study, using microarray chips and surface pasmon resonance (SPR) technology, we screened 189 antibiotics in order to obtain an inhibitor directly binding to the non-N-terminal domain of HSP90 beta. Finally, we discovered an antibiotic, 7-aminocephalosporanic acid (7ACA), with a K-D value of 6.201 mu M between 7ACA and non-N-terminal domain of HSP90 beta. Besides, 7ACA was predicted to interact with the middle domain (MD) of HSP90 beta. In HepG2 cells, we found that 7ACA reduced cellular total cholesterol (TC) and triglyceride (TG) by decreasing sterol regulatory element-binding proteins (SREBPs). In HFD fed mice, administration of 7ACA (5, 10, and 25 mg kg(-1) d(-1), ig, for 12 weeks) dose-dependently decreased serum TC and TG and played an important role in protecting liver and adipose tissue from lipid accumulation. In conclusion, our study demonstrated that antibiotic 7ACA, as an HSP90 beta middle domain inhibitor, was promising for the development of lipid-lowering drugs. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study discovered an antibiotic, 7-aminocephalosporanic acid (7ACA), as an inhibitor of the middle domain of HSP90 beta, showing promise for lipid-lowering drugs. The experimental results demonstrated that 7ACA reduced cellular total cholesterol and triglyceride levels in HepG2 cells and dose-dependently decreased serum cholesterol and triglyceride in mice fed with a high-fat diet.