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Jin Chen, Li Xu, Xue-Qing Zhang, Xue Liu, Zi-Xuan Zhang, Qiu-Mei Zhu, Jian-Yu Liu, Muhammad Omer Iqbal, Ning Ding, Chang-Lun Shao, Mei-Yan Wei, Yu-Chao Gu. 2023: Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis. Marine Life Science & Technology, 5(2): 196-210. DOI: 10.1007/s42995-023-00168-z
Citation: Jin Chen, Li Xu, Xue-Qing Zhang, Xue Liu, Zi-Xuan Zhang, Qiu-Mei Zhu, Jian-Yu Liu, Muhammad Omer Iqbal, Ning Ding, Chang-Lun Shao, Mei-Yan Wei, Yu-Chao Gu. 2023: Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis. Marine Life Science & Technology, 5(2): 196-210. DOI: 10.1007/s42995-023-00168-z

Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis

  • Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A (CHNQD-0803). Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a KD value of 4.728×10–8 M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition, LPS-stimulated inflammation, TGF-β-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.
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