A novel arctigenin derivative attenuates nonalcoholic fatty liver disease by activating adiponectin receptor 1-mediated AMPK signaling pathway

  • Eur J Pharmacol. 2026 Mar 28:1019:178694. doi: 10.1016/j.ejphar.2026.178694.
Shangming Li  1 ,  Siyao Li  2 ,  Xiao Yang  3 ,  Bocheng Xiong  3 ,  Lulin Nie  3 ,  Kaiwu He  3 ,  Mo Li  3 ,  Peimao Li  4 ,  Zaijun Zhang  5 ,  Xifei Yang  6 ,  Maggie Pui Man Hoi  7
Affiliations
  • 1. Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao Special Administrative Region of China; Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 2. College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
  • 3. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 4. Medical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China.
  • 5. Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, Guangdong, China.
  • 6. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China. Electronic address: [email protected].
  • 7. Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao Special Administrative Region of China. Electronic address: [email protected].
PMID: 41765270 DOI: 10.1016/j.ejphar.2026.178694
Abstract

Nonalcoholic fatty liver disease (NAFLD), along with metabolic syndrome and obesity, has seen a dramatic rise in frequency around the world. Arctigenin (ATG) has better efficacy in the treatment of non-alcoholic fatty liver in vitro, but its application in vivo models is limited due to its low oral bioavailability and poor water solubility. Compound ARC-18 is a derivative of ATG. As a prodrug, it improves the bioavailability and solubility of ATG, so that ARC-18 can also have better pharmacological activity in oral administration. The main purpose of this article is to explore the therapeutic effect of compound ARC-18 in nonalcoholic steatohepatitis and its possible mechanism. C57BL/6 J mice were fed with methionine and choline deficient (MCD) diet for 8 weeks to induce NAFLD and were given ARC-18 by gavage for 6 weeks (Proteomics Analysis and Histopathological analysis). The effect of ARC-18 was also investigated in AML12 cells exposed to palmitic acid. Our study showed that ARC-18 (33.0 mg/kg body weight) improved hepatic lipid accumulation, inflammatory damage and liver fibrosis in MCD diet feeding mice. Proteomic analyses indicated that ARC-18 exerts beneficial effects on inflammation, oxidative stress, and lipid metabolism. ARC-18 decreased lipid accumulation and promoted lipid oxidation by activating Adiponectin Receptor 1 (Adipo1 receptor) -mediated Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in vivo and vitro. Our data implies that ARC-18 is a therapeutic medication for the treatment of NAFLD, and that this protective effect is achieved by activating the hepatic Adipo1 receptor-mediated AMPK signaling pathway.

Keywords
AMPK; Adipo1 receptor; Arctigenin derivative; Lipid accumulation; Lipid oxidation; NAFLD.
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