{"title":"黄芪甲苷通过靶向酮己糖激酶Asn261/Ala226维持肠道干细胞稳态,缓解果糖诱导的肠道代谢衰老","authors":"Qifang Wu, , , Yingna Li, , , Yunyun Zhao, , , Ruifen Zhang, , , Jingyang Tong, , , Chunlei Ji, , , Yiming Zhao, , , Mingjiang Wu, , , Xiaosheng Jin, , , Dandan Wang*, , , Haibin Tong*, , , Liwei Sun*, , and , Fangbing Liu*, ","doi":"10.1021/acscentsci.5c00726","DOIUrl":null,"url":null,"abstract":"<p >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 <i>Astragalus membranaceus</i>, 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 <i>Drosophila</i>, 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.</p><p >We discovered KHK as a novel target of Astragaloside IV, which alleviates fructose-induced intestinal metabolic senescence by binding to Asn261 and Ala226 residues in KHK.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1682–1699"},"PeriodicalIF":10.4000,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00726","citationCount":"0","resultStr":"{\"title\":\"Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261/Ala226 to Preserve Intestinal Stem Cell Homeostasis\",\"authors\":\"Qifang Wu, , , Yingna Li, , , Yunyun Zhao, , , Ruifen Zhang, , , Jingyang Tong, , , Chunlei Ji, , , Yiming Zhao, , , Mingjiang Wu, , , Xiaosheng Jin, , , Dandan Wang*, , , Haibin Tong*, , , Liwei Sun*, , and , Fangbing Liu*, \",\"doi\":\"10.1021/acscentsci.5c00726\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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 <i>Astragalus membranaceus</i>, 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 <i>Drosophila</i>, 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.</p><p >We discovered KHK as a novel target of Astragaloside IV, which alleviates fructose-induced intestinal metabolic senescence by binding to Asn261 and Ala226 residues in KHK.</p>\",\"PeriodicalId\":10,\"journal\":{\"name\":\"ACS Central Science\",\"volume\":\"11 9\",\"pages\":\"1682–1699\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2025-07-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00726\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Central Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscentsci.5c00726\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.5c00726","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
过量摄入果糖会导致肠道衰老并损害肠道干细胞(ISC)功能,但有效的治疗干预措施仍然难以捉摸。黄芪甲苷(Astragaloside IV, AS-IV)是一种从黄芪中提取的天然皂苷,具有抗衰老、抗炎和保护肠道的作用。在这里,我们发现AS-IV通过直接抑制酮己糖激酶(KHK)来缓解果糖诱导的肠道代谢衰老,KHK是果糖代谢的关键限速酶。分子对接和定点诱变鉴定出Asn261和Ala226是as - iv在KHK上不同的结合位点,Asn261也是KHK活性必需的关键催化残基。Asn261突变破坏了KHK酶的功能,减少了果糖衍生代谢物如棕榈酸和神经酰胺的积累,从而阻止了果糖诱导的ISC循环停滞。AS-IV的治疗效果在果蝇、小鼠肠道类器官和小鼠中得到了验证,在这些治疗中,治疗一致地逆转了高果糖诱导的肠道代谢衰老表型,恢复了ISC增殖,并保持了ISC稳态。这些发现表明KHK是AS-IV先前未被识别的分子靶点,并揭示了AS-IV调节果糖代谢干扰肠道衰老的保守机制。我们的研究结果强调了它在治疗果糖驱动的肠道衰老和相关代谢紊乱方面的治疗潜力。我们发现KHK是黄芪甲苷IV的新靶点,它通过结合KHK中的Asn261和Ala226残基来缓解果糖诱导的肠道代谢衰老。
Astragaloside IV Alleviates Fructose-Induced Intestinal Metabolic Senescence by Targeting Ketohexokinase Asn261/Ala226 to Preserve Intestinal Stem Cell Homeostasis
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.
We discovered KHK as a novel target of Astragaloside IV, which alleviates fructose-induced intestinal metabolic senescence by binding to Asn261 and Ala226 residues in KHK.
期刊介绍:
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.