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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mafld ; Mash ; Nash ; Cell Death ; Metabolic Syndrome; Choline-deficient Diet; Fatty Liver; Steatohepatitis; Rosiglitazone; Cells; Obese
ISSN (print) / ISBN 2471-254X
e-ISSN 2471-254X
Zeitschrift Hepatology communications
Quellenangaben Band: 9, Heft: 6, Seiten: , Artikelnummer: e0684 Supplement: ,
Verlag Wiley
Verlagsort Hoboken, NJ
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
Förderungen
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