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

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.

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…As one of the important RCDs regulating homeostasis of organisms, ferroptosis plays an intricate role in human health. The onset of some diseases is considered to be related to ferroptosis . Therefore, improving the specificity and controlling the dosage of ferroptosis inducers are essential for reducing adverse effect on healthy tissues.…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…When Se in GPX4 was replaced by sulfur, GPX4 loses its ability to inhibit ferroptosis and caused death in a mouse model . Remarkably, pharmacological Se supplementation effectively inhibits GPX4dependent ferroptotic death as well as cell death induced by excitotoxicity or endoplasmic reticulum (ER) stress, which is GPX4 independent (Alim et al, 2019). Collectively, GPX4 synthesis and the function-related pathway are essential in ferroptosis regulation.…”

“…Particularly, recent research found that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant GSH peroxidase 4 (GPX4). A single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model (Alim et al, 2019). Friedreich ataxia (FRDA) is a progressive neurological and cardiac degenerative disease caused by repeated amplification of GAA in the first intron of two alleles of the FXN gene.…”

Green chicory leaf extract exerts anti-inflammatory effects through suppressing LPS-induced MAPK/NF-κB activation and hepatoprotective activity in vitro

“…MTT assay widely used for evaluating cell viability assay (Alim et al, 2019;Cásedas, González-Burgos, Smith, López, & Gómez-Serranillos, 2018;Miao et al, 2019). RAW 264.7 cells were damaged by LPS while CLE significantly attenuated cell death at the concentration of 10 μg/mL and completely restored cell viability from the concentration of 100 μg/mL.…”