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Semaglutide, a glucagon\u2010like peptide\u20101 (GLP\u20101) 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\u2009nM significantly attenuated lipid deposition caused by FFAs and reduced triglyceride levels by 8\u2010fold and cholesterol levels by 1.8\u2010fold. It also inhibited the expression of pro\u2010inflammatory markers (IL\u20106, IL\u20108, TNF\u2010\u03b1) by about 1.5\u20132 fold and increased the level of lipolytic genes by about 45%. These findings elucidate the therapeutic potential of semaglutide in attenuating key NAFLD\u2010associated pathologies and establish a robust in\u00a0vitro platform for preclinical drug evaluation. The study provides critical insights into targeted NAFLD interventions and supports the translation of GLP\u20101\u2010based therapies into clinical practice, addressing an unmet need in hepatology.<\/jats:p>","DOI":"10.1111\/cpr.70118","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T05:40:37Z","timestamp":1756359637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Development of\n                    <scp>NAFLD<\/scp>\n                    \u2010Specific Human Liver Organoid Models on a Microengineered Array Chip for Semaglutide Efficacy Evaluation"],"prefix":"10.1111","volume":"59","author":[{"given":"Xiao\u2010yan","family":"You","sequence":"first","affiliation":[{"name":"Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering Henan University of Science and Technology  Luoyang China"},{"name":"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"},{"name":"Haihe Laboratory of Synthetic Biology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang\u2010yang","family":"Li","sequence":"additional","affiliation":[{"name":"Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering Henan University of Science and Technology  Luoyang China"},{"name":"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"},{"name":"Haihe Laboratory of Synthetic Biology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"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"},{"name":"School of Life Sciences, Faculty of Medicine, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures Tianjin University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010ping","family":"Zhao","sequence":"additional","affiliation":[{"name":"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"},{"name":"CAS\u2010Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences Institute of Plant Physiology and Ecology, Chinese Academy of Sciences  Shanghai China"},{"name":"CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences  Shenzhen China"},{"name":"Engineering Laboratory for Nutrition Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences  Shanghai P. 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