Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
21 Oct 2024
21 Oct 2024
Historique:
received:
19
03
2024
accepted:
14
10
2024
revised:
10
10
2024
medline:
22
10
2024
pubmed:
22
10
2024
entrez:
21
10
2024
Statut:
epublish
Résumé
Necroptosis and ferroptosis are two distinct forms of necrotic-like cell death in terms of their morphological features and regulatory mechanisms. These two types of cell death can coexist in disease and contribute to pathological processes. Inhibition of both necroptosis and ferroptosis has been shown to enhance therapeutic effects in treating complex necrosis-related diseases. However, targeting both necroptosis and ferroptosis by a single compound can be challenging, as these two forms of cell death involve distinct molecular pathways. In this study, we discovered that KW-2449, a previously described necroptosis inhibitor, also prevented ferroptosis both in vitro and in vivo. Mechanistically, KW-2449 inhibited ferroptosis by targeting the autophagy pathway. We further identified that KW-2449 functioned as a ULK1 (Unc-51-like kinase 1) inhibitor to block ULK1 kinase activity in autophagy. Remarkably, we found that Necrostatin-1, a classic necroptosis inhibitor that has been shown to prevent ferroptosis, also targets the autophagy pathway to suppress ferroptosis. This study provides the first understanding of how necroptosis inhibitors can prevent ferroptosis and suggests that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. Therefore, the identification and design of pharmaceutical molecules that target the autophagy pathway from necroptosis inhibitors is a promising strategy to develop dual inhibitors of necroptosis and ferroptosis in clinical application.
Identifiants
pubmed: 39433736
doi: 10.1038/s41419-024-07157-9
pii: 10.1038/s41419-024-07157-9
doi:
Substances chimiques
Autophagy-Related Protein-1 Homolog
EC 2.7.11.1
necrostatin-1
0
Imidazoles
0
Indoles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
764Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 32170748
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82204481
Organisme : Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)
ID : 21490714300
Organisme : Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)
ID : 22ZR1448000
Informations de copyright
© 2024. The Author(s).
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