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

  • Author(s): Alim, Ishraq
  • Caulfield, Joseph T
  • Chen, Yingxin
  • Swarup, Vivek
  • Geschwind, Daniel H
  • Ivanova, Elena
  • Seravalli, Javier
  • Ai, Youxi
  • Sansing, Lauren H
  • Ste Marie, Emma J
  • Hondal, Robert J
  • Mukherjee, Sushmita
  • Cave, John W
  • Sagdullaev, Botir T
  • Karuppagounder, Saravanan S
  • Ratan, Rajiv R
  • et al.
Abstract

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.

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