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Angendohr, C.* ; Koppe, C.* ; Herebian, D.* ; Schneider, A.T.* ; Keysberg, L.S.* ; Singer, M.T.* ; Gilljam, J.* ; Dille, M.A.* ; Bode, J.G.* ; Doll, S. ; Conrad, M. ; Vucur, M.* ; Luedde, T.*

The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD.

Hepat. Commun. 9:e0684 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition and a major risk factor for chronic liver damage, potentially leading to steatohepatitis and HCC. It is already known that patients with MASLD show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting the involvement of ferroptosis in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD. METHODS: We investigated whether liver parenchymal cell-specific deletion (LPC-KO) of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) reduces MASLD onset and progression in mice. ACSL4LPC-KO and wild-type littermates were fed a choline-deficient high-fat diet (CD-HFD) or a Western diet for 20 weeks (CD-HFD and Western diet) or 40 weeks (CD-HFD only) to monitor MASLD progression and metabolic syndrome development. RESULTS: In contrast to the recently published studies by Duan et al, our results show no significant differences between ACSL4LPC-KO and wild-type mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (ie, weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response. CONCLUSIONS: Our analyses, therefore, suggest that loss of ACSL4 has no effect on the progression of MASLD induced by CD-HFD or the Western diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with hepatocyte-specific ACSL4LPC-KO should be taken with caution.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mafld ; Mash ; Nash ; Cell Death ; Metabolic Syndrome; Choline-deficient Diet; Fatty Liver; Steatohepatitis; Rosiglitazone; Cells; Obese
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2471-254X
e-ISSN 2471-254X
Journal Hepatology communications
Quellenangaben Volume: 9, Issue: 6, Pages: , Article Number: e0684 Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
Grants
German Cancer Aid (Deutsche Krebshilfe)
German Federal Ministry of Education and Research
Ministry of Culture and Science of the State of North Rhine-Westphalia
German Cancer Aid (Deutsche Kreb-shilfe)
German Research Foundation (DFG)
European Research Council (ERC)
LiSyM Cancer NetworkC-TIP HCC - German Federal Ministry of Education and Research
DFG-funded Clinician Scientist Program FUTURE-4-CSPMM
DFG
German Federal Ministry of Education and Research (BMBF) FERRO-PATH
European Research Council (ERC) under the European Union
DOI 10.1097/HC9.0000000000000684
WOS ID 001489206300001
Scopus ID 105005619545
PubMed ID 40377498
Erfassungsdatum 2025-05-20
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