Saracatinib inhibits necroptosis and ameliorates psoriatic inflammation by targeting MLKL.
Cell Death Dis
; 15(2): 122, 2024 02 08.
Article
in 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinases
/
Psoriasis
/
Quinazolines
/
Benzodioxoles
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Death Dis
/
Cell death and disease
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: