Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

Author:

Peleman Cédric,Hellemans Stig,Veeckmans Geraldine,Arras Wout,Zheng Hao,Koeken Ine,Van San EmilyORCID,Hassannia Behrouz,Walravens Magali,Kayirangwa Edissa,Beyene Nateneal Tamerat,Van Herck Mikhaïl Alfons,De Vos Winnok Harald,Pintelon Isabel,van Nassauw Luc,Oosterlinck Baptiste,Smet Annemieke,Vits Lieve,Dirinck Eveline,Verrijken An,De Man Joris,Van Eyck AnneliesORCID,Kwanten Wilhelmus JosephusORCID,Vonghia Luisa,Driessen Ann,Augustyns KoenORCID,Toyokuni ShinyaORCID,De Winter BenedicteORCID,Van Steenkiste Christophe,Francque Sven,Vanden Berghe TomORCID

Abstract

AbstractThere 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.

Funder

Universiteit Antwerpen

Fonds Wetenschappelijk Onderzoek

Publisher

Springer Science and Business Media LLC

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