Skip to main content
eScholarship
Open Access Publications from the University of California

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.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View