2. Academic Validation
  3. Development of NAFLD-Specific Human Liver Organoid Models on a Microengineered Array Chip for Semaglutide Efficacy Evaluation

Development of NAFLD-Specific Human Liver Organoid Models on a Microengineered Array Chip for Semaglutide Efficacy Evaluation

  • Cell Prolif. 2025 Aug 27:e70118. doi: 10.1111/cpr.70118.
Xiao-Yan You 1 2 3,  Xiang-Yang Li 1 2 3,  Hui Wang 2 4,  Guo-Ping Zhao 2 5 6 7
Affiliations

Affiliations

  • 1 Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, China.
  • 2 Master Lab for Innovative Application of Nature Products, National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, China.
  • 3 Haihe Laboratory of Synthetic Biology, Tianjin, China.
  • 4 School of Life Sciences, Faculty of Medicine, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin University, Tianjin, China.
  • 5 CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.
  • 6 CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 7 Engineering Laboratory for Nutrition, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, P. R. China.
PMID: 40873114 DOI: 10.1111/cpr.70118
Abstract

Progressive non-alcoholic fatty liver disease (NAFLD) may culminate in severe complications, including fibrosis, cirrhosis and hepatocellular carcinoma, yet therapeutic breakthroughs remain elusive, necessitating novel pharmacological strategies. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist clinically approved for type 2 diabetes and obesity management, has demonstrated pleiotropic effects in preclinical NAFLD models. In this study, we investigated semaglutide's therapeutic efficacy and mechanisms in a human liver organoids (hLOs) model of NAFLD. Utilising microengineered array chips, human induced pluripotent stem cells (hiPSCs) were differentiated into hLOs with functional hepatic properties. NAFLD pathology was induced via free fatty acid (FFA) exposure, recapitulating disease hallmarks such as steatosis, inflammatory cytokine elevation and fibrogenic activation. Semaglutide treatment at 50 nM significantly attenuated lipid deposition caused by FFAs and reduced triglyceride levels by 8-fold and Cholesterol levels by 1.8-fold. It also inhibited the expression of pro-inflammatory markers (IL-6, IL-8, TNF-α) by about 1.5-2 fold and increased the level of lipolytic genes by about 45%. These findings elucidate the therapeutic potential of semaglutide in attenuating key NAFLD-associated pathologies and establish a robust in vitro platform for preclinical drug evaluation. The study provides critical insights into targeted NAFLD interventions and supports the translation of GLP-1-based therapies into clinical practice, addressing an unmet need in hepatology.

Keywords

array chip; drug assessment; non‐alcoholic fatty liver; organoid; semaglutide.

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