Discovery of NAFLD-Improving Agents by Promoting the Degradation of Keap1

Activating Nrf2 through inhibiting Keap1 has been proven to alleviate oxidative stress and related diseases, including nonalcoholic fatty liver disease (NAFLD). Traditional Keap1 inhibitors could not avoid the “off-target” effects, but using proteolysis targeting chimera (PROTAC) technology to induce Keap1 degradation might be an effective strategy to find potential NAFLD improving agents. Thus, several PROTACs were designed and synthesized by harnessing CDDO as the Keap1 ligand in this study. PROTAC I-d exhibited optimal Keap1 degradation activity, which could increase the Nrf2 level and alleviate oxidative stress in free fatty acid-induced AML12 cells and the liver of mice fed with a methionine-choline-deficient diet. Moreover, compared with CDDO, PROTAC I-d displayed significant advantages in inhibiting hepatic steatosis, steatohepatitis, and fibrosis in the in vivo and in vitro models of NAFLD. In addition, PROTAC I-d also showed lower in vivo toxicity than CDDO. All these results suggested that PROTAC I-d might be a potential improving agent for NAFLD.