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

  • J Med Chem. 2026 Feb 12;69(3):2509-2538. doi: 10.1021/acs.jmedchem.5c02431.
Zhipeng Zhang  1 ,  Hongyan Lai  1 ,  Shaofang Tian  1 ,  Yingjie Song  1 ,  Cunwuliji Na  1 ,  Xiang Shi  1 ,  Changhong He  1 ,  Liuye Shi  1 ,  Shengyun Wang  1 ,  Fawad Ali  1 ,  Fu Shu  1 ,  Baoshun Zhang  1
Affiliations
  • 1. College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China.
PMID: 41589317 DOI: 10.1021/acs.jmedchem.5c02431
Abstract

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.

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