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

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Název: Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261/Ala226 to Preserve Intestinal Stem Cell Homeostasis
Autoři: Qifang Wu, Yingna Li, Yunyun Zhao, Ruifen Zhang, Jingyang Tong, Chunlei Ji, Yiming Zhao, Mingjiang Wu, Xiaosheng Jin, Dandan Wang, Haibin Tong, Liwei Sun, Fangbing Liu
Rok vydání: 2025
Témata: Biochemistry, Medicine, Cell Biology, Genetics, Molecular Biology, Physiology, Pharmacology, Ecology, Science Policy, Virology, Computational Biology, Space Science, Chemical Sciences not elsewhere classified, distinct binding sites, critical catalytic residue, associated metabolic disorders, asn261 also serving, driven intestinal aging, astragalus membranaceus <, restored isc proliferation, preserved isc homeostasis, thereby prevented fructose, targeting ketohexokinase asn261, iv alleviates fructose, drosophila <, treating fructose, fructose metabolism, widely recognized, validated across, therapeutic potential
Popis: 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.
Druh dokumentu: article in journal/newspaper
Jazyk: unknown
DOI: 10.1021/acscentsci.5c00726.s001
Dostupnost: https://doi.org/10.1021/acscentsci.5c00726.s001
https://figshare.com/articles/journal_contribution/Astragaloside_IV_Alleviates_Fructose-Induced_Intestinal_Metabolic_Senescence_by_Targeting_Ketohexokinase_Asn261_Ala226_to_Preserve_Intestinal_Stem_Cell_Homeostasis/29669336
Rights: CC BY-NC 4.0
Přístupové číslo: edsbas.B25D0704
Databáze: BASE
Popis
Abstrakt: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.
DOI:10.1021/acscentsci.5c00726.s001