Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.
Cell Death Differ
; 31(9): 1113-1126, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-39060422
ABSTRACT
There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ferroptose
/
Fosfolipídeo Hidroperóxido Glutationa Peroxidase
Limite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Cell Death Differ
/
Cell death and differentiation
/
Cell death differ
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Bélgica