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

  • Mar Life Sci Technol. 2023 Apr 30;5(2):196-210. doi: 10.1007/s42995-023-00168-z.
Jin Chen  #  1  2  3 ,  Li Xu  #  1  2 ,  Xue-Qing Zhang  1  2 ,  Xue Liu  1  2  3 ,  Zi-Xuan Zhang  1  2 ,  Qiu-Mei Zhu  1  2  3 ,  Jian-Yu Liu  1  2 ,  Muhammad Omer Iqbal  1  2  3 ,  Ning Ding  4 ,  Chang-Lun Shao  1  2 ,  Mei-Yan Wei  1  5 ,  Yu-Chao Gu  1  2  3
Affiliations
  • 1. Key Laboratory of Marine Drugs, the Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003 China.
  • 2. Laboratory for Marine Drugs and Bioproducts, Laoshan Laboratory, Qingdao, 266237 China.
  • 3. Key Laboratory of Glycoscience and Glycotechnology of Shandong Province, Qingdao, 266003 China.
  • 4. The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114 USA.
  • 5. College of Food Science and Engineering, Ocean University of China, Qingdao, 266003 China.
  • # Contributed equally.
PMID: 37275542 DOI: 10.1007/s42995-023-00168-z
Abstract

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s42995-023-00168-z.

Keywords
AMPK; Fibrosis; Inflammation; Lipid metabolism; Marine drug; NASH.
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