Abstract: Fructose, valued for its intense sweetness and low cost, is widely used as a sweetener and serves as a key component in processed foods and sugar-sweetened beverages. However, excessive fructose intake has been confirmed to be closely associated with the occurrence and progression of various metabolic diseases, such as obesity, diabetes, hypertension, and cancer, and even significantly increases the risk of mortality. Recent studies reveal a ‌dose-dependent dual-pathway mechanism‌ in fructose metabolism. At low doses, fructose is primarily transported via intestinal glucose transporter 5 (GLUT5) located on the apical membrane of intestinal epithelial cells and undergoes first-pass metabolism catalyzed by ketohexokinase-C (KHK-C) into fructose-1-phosphate (F1P), thereby greatly reducing the fructose load entering the systemic circulation. When its intake exceeds the threshold, fructose “spills over” and unmetabolized fructose enters the liver via the portal vein, significantly activating the de novo lipogenesis (DNL) pathway. This process upregulates sterol-regulatory element binding protein-1c (SREBP-1c) and carbohydrate responsive element binding protein (ChREBP), enhancing lipid synthesis and ultimately inducing hepatic and systemic lipid accumulation, obesity, and non-alcoholic fatty liver disease (NAFLD), accompanied by insulin resistance. Mechanistic studies have shown that a high-fructose diet can reshape the composition of the gut microbiota, increasing the abundance of Bacteroidetes and Proteobacteria, while significantly down-regulating the expression of tight junction proteins (occludin, claudin-1, and ZO-1), thereby compromising the intestinal mucosal barrier. This facilitates the translocation of lipopolysaccharide (LPS) and activates Toll-like receptor 4 (TLR4)-mediated systemic low-grade chronic inflammatory responses. Moreover, high fructose intake can increase the production of intermediates in purine metabolism, enhancing uric acid synthesis and impairing vascular endothelial function, thereby exacerbating the onset and progression of hyperuricemia. This review comprehensively delineates the mechanisms of fructose absorption and metabolism and its pathogenic role in metabolic disorders, aiming to offer novel theoretical insights and strategies for targeted interventions.

Key words: fructose metabolism; lipogenesis; gut dysbiosis