Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization
Abstract At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small‐molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropath...
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2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202414587 |
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| author | Chen Xuan Donghui Chen Shuangna Zhang Chaofan Li Qingyun Fang Dinghua Chen Jiabao Liu Xin Jiang Yingjie Zhang Wanjun Shen Guangyan Cai Xiangmei Chen Ping Li |
| author_facet | Chen Xuan Donghui Chen Shuangna Zhang Chaofan Li Qingyun Fang Dinghua Chen Jiabao Liu Xin Jiang Yingjie Zhang Wanjun Shen Guangyan Cai Xiangmei Chen Ping Li |
| author_sort | Chen Xuan |
| collection | DOAJ |
| description | Abstract At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small‐molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropathy; however, the underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation and fibrosis by inhibiting STAT3 activity in mice with diabetic nephropathy. Moreover, STAT3 is a direct molecular target of isoquercitrin, which as corroborated by tight and stable noncovalent binding between them. This interaction is mechanistically supported by the affinity of isoquercitrin for the Ser668–Gln635–Gln633 region within the pY+1 binding pocket of the SH2 domain. This binding obstructs pivotal processes like STAT3 phosphorylation and dimerization, thereby suppressing its transcriptional function. Finally, a kidney‐targeted nanocarrier, Iso@PEG‐GK, is developed to load isoquercitrin, thus enhancing its therapeutic precision for diabetic nephropathy. Iso@PEG‐GK significantly improved the absorption and renal distribution of isoquercitrin. This study is the first to demonstrate that isoquercitrin exerts a significant protective effect against diabetic nephropathy and may provide a novel therapeutic drug for this disease. |
| format | Article |
| id | doaj-art-f1e04eead0f34ac99177f3f7aff7c35c |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-f1e04eead0f34ac99177f3f7aff7c35c2025-08-20T03:30:48ZengWileyAdvanced Science2198-38442025-07-011225n/an/a10.1002/advs.202414587Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and DimerizationChen Xuan0Donghui Chen1Shuangna Zhang2Chaofan Li3Qingyun Fang4Dinghua Chen5Jiabao Liu6Xin Jiang7Yingjie Zhang8Wanjun Shen9Guangyan Cai10Xiangmei Chen11Ping Li12School of Basic Medical Sciences Chengdu University of Traditional Chinese Medicine Chengdu 610075 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaSchool of Basic Medical Sciences Chengdu University of Traditional Chinese Medicine Chengdu 610075 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaDepartment of Nephrology First Medical Center of Chinese PLA General Hospital State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan‐vascular Diseases Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk‐2023310) Beijing 100000 ChinaAbstract At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small‐molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropathy; however, the underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation and fibrosis by inhibiting STAT3 activity in mice with diabetic nephropathy. Moreover, STAT3 is a direct molecular target of isoquercitrin, which as corroborated by tight and stable noncovalent binding between them. This interaction is mechanistically supported by the affinity of isoquercitrin for the Ser668–Gln635–Gln633 region within the pY+1 binding pocket of the SH2 domain. This binding obstructs pivotal processes like STAT3 phosphorylation and dimerization, thereby suppressing its transcriptional function. Finally, a kidney‐targeted nanocarrier, Iso@PEG‐GK, is developed to load isoquercitrin, thus enhancing its therapeutic precision for diabetic nephropathy. Iso@PEG‐GK significantly improved the absorption and renal distribution of isoquercitrin. This study is the first to demonstrate that isoquercitrin exerts a significant protective effect against diabetic nephropathy and may provide a novel therapeutic drug for this disease.https://doi.org/10.1002/advs.202414587diabetic nephropathyisoquercitrinIso@PEG‐GKSTAT3SH2 domainphosphorylation |
| spellingShingle | Chen Xuan Donghui Chen Shuangna Zhang Chaofan Li Qingyun Fang Dinghua Chen Jiabao Liu Xin Jiang Yingjie Zhang Wanjun Shen Guangyan Cai Xiangmei Chen Ping Li Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization Advanced Science diabetic nephropathy isoquercitrin Iso@PEG‐GK STAT3 SH2 domain phosphorylation |
| title | Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization |
| title_full | Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization |
| title_fullStr | Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization |
| title_full_unstemmed | Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization |
| title_short | Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization |
| title_sort | isoquercitrin alleviates diabetic nephropathy by inhibiting stat3 phosphorylation and dimerization |
| topic | diabetic nephropathy isoquercitrin Iso@PEG‐GK STAT3 SH2 domain phosphorylation |
| url | https://doi.org/10.1002/advs.202414587 |
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