Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis

• Type of Material: Article
• Authors: Hui Tao, Emory University; Hamid Y. Dar, Emory University; Cheng Tian, St. Jude Children's Research Hospital; Somesh Banerjee, Emory University; Evan S. Glazer, The University of Tennessee; Shanthi Srinivasan, Emory University; Liqin Zhu, St. Jude Children's Research Hospital; Roberto Pacifici, Emory University; Peijian He, Emory University
• Language: English
• Date: 2023-09-17
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016%2Fj.redox.2023.102892
• Title of Journal or Parent Work: Redox Biology
• Volume: 67
• Start Page: 102892
• Grant/Funding Information: This study was supported by National Institute of Health grant R01DK125647.
• Keywords: FSP1; Mitochondrial ROS; Ovariectomy; Mfrn1; FTH1; Antioxidant defense
• Research Categories: Biology, Cell

Abstract

Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.