Design, Synthesis, and Biological Evaluation of Chromone Derivatives as STAT1 Inhibitors for Treatment of Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with a high global incidence rate, intricately linked to metabolic disorders. It is characterized by steatosis, inflammation, and hepatocyte ballooning. STAT1 is a transcription factor involved in metabolic regulation and progression of inflammatory responses. In this study, we have identified STAT1 as a novel therapeutic target for NASH. Using our established STAT1 inhibitor screening platform, we identified the compound ZDZ-553, which is characterized by a chromone skeleton, demonstrates potent inhibitory activity against STAT1, and exhibits a favorable safety profile. In the NASH mouse model experiment, ZDZ-553 significantly ameliorated liver steatosis and inflammatory responses. These findings collectively suggest that ZDZ-553 could be a promising candidate for treatment of NASH, highlighting the therapeutic potential of targeting STAT1.