2. Academic Validation
  3. A novel arctigenin derivative attenuates nonalcoholic fatty liver disease by activating adiponectin receptor 1-mediated AMPK signaling pathway

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

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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