Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261/Ala226 to Preserve Intestinal Stem Cell Homeostasis

  • ACS Cent Sci. 2025 Jul 29;11(9):1682-1699. doi: 10.1021/acscentsci.5c00726.
Qifang Wu  1 ,  Yingna Li  1 ,  Yunyun Zhao  2 ,  Ruifen Zhang  3 ,  Jingyang Tong  3 ,  Chunlei Ji  1 ,  Yiming Zhao  1 ,  Mingjiang Wu  3 ,  Xiaosheng Jin  4 ,  Dandan Wang  1 ,  Haibin Tong  3 ,  Liwei Sun  1 ,  Fangbing Liu  5
Affiliations
  • 1. Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China.
  • 2. Department of Endocrinology and Metabolism, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, China.
  • 3. College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
  • 4. Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China.
  • 5. Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130021, China.
PMID: 41019116 DOI: 10.1021/acscentsci.5c00726
Abstract

Excessive fructose intake drives intestinal aging and impairs intestinal stem cell (ISC) function, yet effective therapeutic interventions remain elusive. Astragaloside IV (AS-IV), a natural saponin from Astragalus membranaceus, has been widely recognized for its antiaging, anti-inflammatory, and gut-protective properties. Here, we revealed that AS-IV alleviates fructose-induced intestinal metabolic senescence via direct inhibition of Ketohexokinase (KHK), the key rate-limiting enzyme in fructose metabolism. Molecular docking and site-directed mutagenesis identified Asn261 and Ala226 as distinct binding sites for AS-IV on KHK, with Asn261 also serving as a critical catalytic residue that is essential for KHK activity. Mutation at Asn261 abolished KHK enzymatic function, reduced the accumulation of fructose-derived metabolites such as palmitic acid and ceramide, and thereby prevented fructose-induced ISC cycle arrest. AS-IV's therapeutic efficacy was validated across Drosophila, murine intestinal organoids, and mice, where treatment consistently reversed high-fructose-induced intestinal metabolic senescence phenotypes, restored ISC proliferation, and preserved ISC homeostasis. These findings indicate that KHK is a previously unrecognized molecular target of AS-IV and reveal a conserved mechanism by which AS-IV modulates fructose metabolism to interfere with gut aging. Our results highlight its therapeutic potential in treating fructose-driven intestinal aging and associated metabolic disorders.

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