Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL
Abstract Necroptosis is a kind of programmed cell death that causes the release of damage-associated molecular patterns and inflammatory disease including skin inflammation. Activation of receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLK...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06514-y |
| _version_ | 1797273074468388864 |
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| author | Jingyi Li Xingfeng Liu Yuanyuan Liu Fangmin Huang Jiankun Liang Yingying Lin Fen Hu Jianting Feng Zeteng Han Yushi Chen Xuan Chen Qiaofa Lin Lanqin Wu Lisheng Li |
| author_facet | Jingyi Li Xingfeng Liu Yuanyuan Liu Fangmin Huang Jiankun Liang Yingying Lin Fen Hu Jianting Feng Zeteng Han Yushi Chen Xuan Chen Qiaofa Lin Lanqin Wu Lisheng Li |
| author_sort | Jingyi Li |
| collection | DOAJ |
| description | Abstract Necroptosis is a kind of programmed cell death that causes the release of damage-associated molecular patterns and inflammatory disease including skin inflammation. Activation of receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) is the hallmark of tumour necrosis factor α (TNF)-induced necroptosis. Here, we screened a small-molecule compound library and found that saracatinib inhibited TNF-induced necroptosis. By targeting MLKL, Saracatinib interfered with the phosphorylation, translocation, and oligomerization of MLKL induced by TNF. Consistently, mutation of the saracatinib-binding site of MLKL reduced the inhibitory effect of saracatinib on TNF-induced necroptosis. In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis. |
| first_indexed | 2024-03-07T14:38:23Z |
| format | Article |
| id | doaj.art-fd4d39e079414bb1a39e9656787173dc |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:23Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-fd4d39e079414bb1a39e9656787173dc2024-03-05T20:30:53ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211110.1038/s41419-024-06514-ySaracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKLJingyi Li0Xingfeng Liu1Yuanyuan Liu2Fangmin Huang3Jiankun Liang4Yingying Lin5Fen Hu6Jianting Feng7Zeteng Han8Yushi Chen9Xuan Chen10Qiaofa Lin11Lanqin Wu12Lisheng Li13The School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityThe School of Basic Medical Sciences, Fujian Medical UniversityAbstract Necroptosis is a kind of programmed cell death that causes the release of damage-associated molecular patterns and inflammatory disease including skin inflammation. Activation of receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) is the hallmark of tumour necrosis factor α (TNF)-induced necroptosis. Here, we screened a small-molecule compound library and found that saracatinib inhibited TNF-induced necroptosis. By targeting MLKL, Saracatinib interfered with the phosphorylation, translocation, and oligomerization of MLKL induced by TNF. Consistently, mutation of the saracatinib-binding site of MLKL reduced the inhibitory effect of saracatinib on TNF-induced necroptosis. In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis.https://doi.org/10.1038/s41419-024-06514-y |
| spellingShingle | Jingyi Li Xingfeng Liu Yuanyuan Liu Fangmin Huang Jiankun Liang Yingying Lin Fen Hu Jianting Feng Zeteng Han Yushi Chen Xuan Chen Qiaofa Lin Lanqin Wu Lisheng Li Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL Cell Death and Disease |
| title | Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL |
| title_full | Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL |
| title_fullStr | Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL |
| title_full_unstemmed | Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL |
| title_short | Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL |
| title_sort | saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting mlkl |
| url | https://doi.org/10.1038/s41419-024-06514-y |
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