Intestinal-specific ketohexokinase deficiency ameliorates high fructose-induced metabolic dysfunction across the intestinal-liver-kidney axis in mice.

The small intestine, one of the three major sites for ketohexokinase (KHK, also known as fructokinase) expression, plays a crucial role in fructose-related pathological processes, primarily by regulating fructose absorption and its subsequent transport to the liver. However, the direct evidence regarding the importance of intestinal KHK on metabolic syndrome caused by fructose alone remains lacking. In this study, we found that intestinal-specific Khk deletion in mice significantly alleviated metabolic syndrome phenotypes induced by 20% fructose drinking solution. These improvements included reduced hepatic steatosis and liver injury, improved glucose and insulin resistance, enhanced colonic epithelial barrier integrity, and attenuated adipose tissue remodeling. Mechanistically, intestinal-specific Khk deletion in fructose-challenged mice is associated with reduced fructose exposure, which likely contributes substantially to three key downstream outcomes: (1) decreased uric acid production via the intestinal-liver-kidney axis; (2) preserved jejunal zinc homeostasis; and (3) suppressed hepatic triglyceride and fatty acid biosynthesis, thereby driving the observed metabolic benefits. Our findings highlight intestinal KHK as a critical mediator in high-fructose-induced metabolic syndrome across the intestinal-liver-kidney axis. Selective targeting of intestinal KHK could represent a promising therapeutic approach for managing metabolic syndrome associated with excessive fructose intake.