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.