1. Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL.
- Author
-
Li J, Liu X, Liu Y, Huang F, Liang J, Lin Y, Hu F, Feng J, Han Z, Chen Y, Chen X, Lin Q, Wu L, and Li L
- Subjects
- Mice, Animals, Necroptosis, Apoptosis, Inflammation metabolism, Transcription Factors metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Protein Kinases genetics, Protein Kinases metabolism, Psoriasis chemically induced, Psoriasis drug therapy, Quinazolines, Benzodioxoles
- 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., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF