Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL.
Cell Death Dis
; 15(2): 122, 2024 02 08.
Article
em En
| MEDLINE
| ID: mdl-38331847
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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Psoríase
/
Quinazolinas
/
Benzodioxóis
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2024
Tipo de documento:
Article