Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke

Cell. 2019 May 16;177(5):1262-1279.e25. doi: 10.1016/j.cell.2019.03.032. Epub 2019 May 2.


Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

Keywords: GPX4; adaptation; cell death; ferroptosis; intracerebral hemorrhage; selenium; selenoprotein; stroke; therapeutic peptides; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia* / drug therapy
  • Brain Ischemia* / metabolism
  • Brain Ischemia* / pathology
  • Cell-Penetrating Peptides / pharmacology*
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • Ferroptosis / drug effects*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Intracranial Hemorrhages* / drug therapy
  • Intracranial Hemorrhages* / metabolism
  • Intracranial Hemorrhages* / pathology
  • Male
  • Mice
  • Neurons* / metabolism
  • Neurons* / pathology
  • Phospholipid Hydroperoxide Glutathione Peroxidase / biosynthesis*
  • Selenium / pharmacology*
  • Sp1 Transcription Factor / metabolism
  • Stroke* / drug therapy
  • Stroke* / metabolism
  • Stroke* / pathology
  • Transcription Factor AP-2 / metabolism
  • Transcription, Genetic / drug effects*


  • Cell-Penetrating Peptides
  • Sp1 Transcription Factor
  • Tfap2c protein, mouse
  • Transcription Factor AP-2
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • Selenium