ORIGINAL RESEARCH article
Front. Nutr.
Sec. Nutrigenomics
This article is part of the Research TopicPrecision Nutrition and Dietary Interventions in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)View all 3 articles
Identification of the Role of Sugar-Sweetened Beverages in the Progression of a Murine Metabolic Dysfunction-Associated Steatotic Liver Disease Model
Provisionally accepted
- 1The First Affiliated Hospital of Jinan University, Guangzhou, China
- 2School of Medicine, South China University of Technology, Guangzhou, China
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Background: Rising metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence parallels increased sugar-sweetened beverage (SSB) consumption. Clinical studies suggest differential metabolic effects of fructose, glucose, and sucrose, yet their distinct roles in MASLD pathogenesis remain uncharacterized in preclinical models. This study aimed to establish a murine model to dissect the specific contributions of fructose, glucose, and sucrose to MASLD progression. Methods: This study establishes a murine model to dissect SSB-specific contributions to MASLD progression. Eight-week-old male C57BL/6N mice were fed a high-fat high-cholesterol (HFHC) diet with/without fructose-, glucose-, or sucrose-sweetened beverages for 10 weeks. Hepatic transcriptomic profiles were analyzed via microarray, followed by functional enrichment. protein-protein interaction (PPI) network and single-cell analysis identify pathway perturbations and hub genes. Results: Fructose-SB supplementation, unlike glucose or sucrose, exacerbated HFHC-induced MASLD phenotypes, including elevated body weight, hepatic steatosis, glucose intolerance, and hepatocellular injury. Transcriptomics identified 2,195 fructose-specific differentially expressed genes (DEGs: 1,978 upregulated, 224 downregulated). Upregulated DEGs were enriched in thyroid hormone signaling, lysosomal activity, and autophagy, while downregulated DEGs implicated oxidative phosphorylation suppression. PPI analysis revealed key hub genes (Akt1, Stat3, Ctnnb1, Ep300) and mitochondrial components (mt-Nd4, mt-Cytb, Uqcrq) as central regulators of fructose-driven pathology. Fructose-SB uniquely accelerates MASLD progression in HFHC-fed mice through transcriptional reprogramming of metabolic and mitochondrial pathways. In mice fed a high-fructose diet, expression of key hub genes was elevated, particularly in Kupffer and endothelial cells, which were also enriched in proportion. These findings highlight fructose-specific mechanisms in MASLD pathogenesis and identify potential therapeutic targets for SSB-associated metabolic disorders.
Keywords: MASLD1, fructose2, sugar-sweetened beverages3, bioinformatics analysis4, dietaryinterventions5
Received: 22 Sep 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Li, Huang, Chen, Yang, Cheng, Chen and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yongjian Zhou, yongjian_zhou@outlook.com
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