Identification of RIPK3 as a target of flavonoids for anti-necroptosis in vitro
文献类型：期刊论文
| 作者 | Xie, Hang6; Li, Wanchen5; Han, Xiaoyu7,8; Li, Minjun1; Zhao, Qiang6,7,8 ; Xu, Yechun6,7,8,9; Su, Haixia7,8; Meng, Weihua2,3,4,5
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| 刊名 | BIOORGANIC CHEMISTRY
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| 出版日期 | 2025-07-01 |
| 卷号 | 161页码:11 |
| 关键词 | RIPK3 Inhibitors Flavonoids Co-crystal structure Anti-necroptosis effect |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2025.108503 |
| 英文摘要 | Receptor-interacting protein kinase 3 (RIPK3), a key regulator of necroptosis, has emerged as an important target for therapeutic intervention. Flavonoids are natural compounds known for their anti-inflammatory and antioxidant properties, with recent studies highlighting their potential to modulate necroptosis. In this study, we explored the potential of RIPK3 as a target for flavonoids to achieve anti-necroptosis and anti-inflammatory effects. A library of 63 flavonoids was tested for RIPK3 binding and kinase inhibition using fluorescence polarization (FP) competition assay and ADP-Glo kinase activity assay. Six flavonoids, including scutellarein, robinetin, baicalin, myricetin, baicalein, and tricetin, showed significant inhibition of RIPK3, with IC50 values ranging from 2.5 to 13.7 mu M. Structural studies of tricetin and robinetin through co-crystallization and molecular docking revealed distinct binding modes of these flavonoids within the ATP-binding pocket of RIPK3. The antinecroptosis effects of these flavonoids were further evaluated in human HT-29 cells and mouse embryonic fibroblasts (MEFs) using a TSZ-induced cell death assay, resulting in EC50 values in the tens of micromolar range. Western blot analysis demonstrated that these flavonoids inhibit the phosphorylation of RIPK3 and its downstream effector, mixed lineage kinase domain-like protein (MLKL), and disrupt the formation of RIPK1 and RIPK3 aggregates in the necroptosis pathway. These findings identify RIPK3 as a target of natural flavonoids for the first time and elucidate the molecular mechanism underlying the anti-necroptotic activity of these flavonoids. |
| WOS关键词 | MIXED LINEAGE KINASE ; DOMAIN-LIKE ; CELL-DEATH ; PROTEIN ; MLKL ; INFLAMMATION ; DOWNSTREAM ; PARAMETERS ; APOPTOSIS ; ACCURACY |
| 资助项目 | Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; Research Program of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SKLDR-2024-TT-03] ; Pioneer and Leading Goose R & D Program of Zhejiang Province[2023C04049] ; Ningbo Inter-national Collaboration Program[2023H025] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001487369300001 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317926]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xu, Yechun; Su, Haixia; Meng, Weihua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China 2.Queens Univ Belfast, Fac Med Hlth & Life Sci, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast BT12 6BA, North Ireland 3.Univ Dundee, Med Sch, Dundee DD2 4BF, Scotland 4.Univ Dundee, Ninewells Hosp, Div Populat Hlth & Genom, Dundee DD2 4BF, Scotland 5.Univ Nottingham Ningbo China, Nottingham Ningbo China Beacons Excellence Res & I, Ningbo 315100, Peoples R China 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 9.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Hang,Li, Wanchen,Han, Xiaoyu,et al. Identification of RIPK3 as a target of flavonoids for anti-necroptosis in vitro[J]. BIOORGANIC CHEMISTRY,2025,161:11. |
| APA | Xie, Hang.,Li, Wanchen.,Han, Xiaoyu.,Li, Minjun.,Zhao, Qiang.,...&Meng, Weihua.(2025).Identification of RIPK3 as a target of flavonoids for anti-necroptosis in vitro.BIOORGANIC CHEMISTRY,161,11. |
| MLA | Xie, Hang,et al."Identification of RIPK3 as a target of flavonoids for anti-necroptosis in vitro".BIOORGANIC CHEMISTRY 161(2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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