RRC ID 57549
Author Park SJ, Cho SS, Kim KM, Yang JH, Kim JH, Jeong EH, Yang JW, Han CY, Ku SK, Cho IJ, Ki SH.
Title Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury.
Journal Toxicol Appl Pharmacol
Abstract Ferroptosis is the non-apoptotic form of cell death caused by small molecules or conditions that inhibit glutathione biosynthesis or resulting in iron-dependent accumulation of lipid peroxidation by lipid reactive oxygen species (ROS). Sestrin2 (Sesn2), a conserved antioxidant protein, is responsive to various stresses including genotoxic, metabolic, and oxidative stresses and acts to restore homeostatic balance. Sesn2 expression was reported to be regulated via stress-responsive transcription factors including p53, Nrf2, and HIF-1α. However, the role of Sesn2 in regulating ferroptosis is not known. In the current study, we investigated whether ferroptosis inducing compounds including erastin, sorafenib, and buthionine sulfoximine affect Sesn2 expression and the role of Sesn2 in cytoprotection against ferroptosis-mediated cell death. Our data demonstrate that ferroptosis inducers significantly increased Sesn2 in hepatocytes in a dose- and time-dependent manner. Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Furthermore, deletion of the antioxidant response element (ARE) in the Sesn2 promoter or Nrf2 knockout or knockdown abolished erastin-induced Sesn2 expression. In cells expressing Sesn2, erastin-induced cell death, ROS formation, and glutathione depletion were almost completely inhibited compared to that in control cells. Treatment with phenylhydrazine in mice, well-reported iron overload liver injury model, increased ALT and AST levels and altered histological features, which were almost completely inhibited by adenoviral Sesn2 infection. Collectively, our results suggest that ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.
Volume 379
Pages 114665
Published 2019-9-15
DOI 10.1016/j.taap.2019.114665
PII S0041-008X(19)30273-X
PMID 31323261
MeSH Animals Chemical and Drug Induced Liver Injury / metabolism* Chemical and Drug Induced Liver Injury / pathology Ferroptosis* Glutathione / metabolism Hep G2 Cells Hepatocytes / metabolism Humans Iron Overload / complications* Iron Overload / metabolism Lipid Peroxidation Liver / metabolism Liver / pathology Male Mice, Inbred ICR Mice, Knockout Nuclear Proteins / metabolism Nuclear Proteins / physiology* Polymerase Chain Reaction Reactive Oxygen Species / metabolism
IF 3.585
Times Cited 3
DNA material pGL4-phSESN2 (RDB07413)