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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 (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.

SUBMITTER: Li J 

PROVIDER: S-EPMC10853205 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL.

Li Jingyi J   Liu Xingfeng X   Liu Yuanyuan Y   Huang Fangmin F   Liang Jiankun J   Lin Yingying Y   Hu Fen F   Feng Jianting J   Han Zeteng Z   Chen Yushi Y   Chen Xuan X   Lin Qiaofa Q   Wu Lanqin L   Li Lisheng L  

Cell death & disease 20240208 2


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, Sa  ...[more]

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