Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH.
Cell Metab
; 2024 Aug 12.
Article
in En
| MEDLINE
| ID: mdl-39142286
ABSTRACT
The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2024
Document type:
Article
Country of publication:
United States