Article
作者: Smet, Annemieke ; Kwanten, Wilhelmus Josephus ; Pintelon, Isabel ; Koeken, Ine ; Augustyns, Koen ; Walravens, Magali ; De Vos, Winnok Harald ; Van Herck, Mikhaïl Alfons ; Dirinck, Eveline ; Vits, Lieve ; Verrijken, An ; Oosterlinck, Baptiste ; Beyene, Nateneal Tamerat ; Hassannia, Behrouz ; Vanden Berghe, Tom ; Hellemans, Stig ; Arras, Wout ; De Winter, Benedicte ; van Nassauw, Luc ; Van San, Emily ; De Man, Joris ; Van Steenkiste, Christophe ; Francque, Sven ; Zheng, Hao ; Peleman, Cédric ; Vonghia, Luisa ; Van Eyck, Annelies ; Toyokuni, Shinya ; Veeckmans, Geraldine ; Driessen, Ann ; Kayirangwa, Edissa
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.
