The IGF2BP3/Notch/Jag1 pathway: A key regulator of hepatic stellate cell ferroptosis in liver fibrosis.
Clin Transl Med
; 14(8): e1793, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-39113232
ABSTRACT
INTRODUCTION:
Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications.OBJECTIVES:
N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. METHODS ANDRESULTS:
This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression.CONCLUSION:
These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. KEY POINTS/HIGHLIGHTS IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Proteínas de Unión al ARN
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Receptores Notch
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Células Estrelladas Hepáticas
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Proteína Jagged-1
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Ferroptosis
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Cirrosis Hepática
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Clin Transl Med
Año:
2024
Tipo del documento:
Article
País de afiliación:
China