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

Ishraq Alim, Joseph T. Caulfield, Yingxin Chen, Vivek Swarup, Daniel H. Geschwind, Elena Ivanova, Javier Seravalli, Youxi Ai, Lauren H. Sansing, Emma J. Emma, Robert J. Hondal, Sushmita Mukherjee, John W. Cave, Botir T. Sagdullaev, Saravanan S. Karuppagounder, Rajiv R. Ratan

Research output: Contribution to journalArticlepeer-review

250 Scopus citations


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. An adaptive response to ferroptotic stress is uncovered and leveraged to develop a neuroprotectant that reduces cell death and improves function after hemorrhagic stroke in mice.

Original languageEnglish (US)
Pages (from-to)1262-1279.e25
Issue number5
StatePublished - May 16 2019


  • GPX4
  • adaptation
  • cell death
  • ferroptosis
  • intracerebral hemorrhage
  • selenium
  • selenoprotein
  • stroke
  • therapeutic peptides
  • transcription

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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