No abstract

Ferroptosis is a form of regulated cell death that is driven by lethal accumulation of lipid peroxides upon inhibition of glutathione peroxidase 4 (GPx4). Deletion of the Gpx4 gene in mice revealed that neurons are sensitive to ferroptosis in vivo. However, few studies have been conducted on ferroptosis regulation in neurons. Here, we report that cells of a motor neuron‐like cell line, NSC‐34, became more sensitive to ferroptosis upon differentiation into a more motor neuron‐like condition. We identified three factors that influence ferroptosis sensitivity under differentiation conditions: low serum antioxidants, decreased GPx4 protein amount, and inhibition of the transsulfuration pathway. Our results support the hypothesis that neurons, especially motor neurons, are sensitive to ferroptosis, and suggest that ferroptosis in a neuronal context should be investigated further to develop strategies for neuroprotection.

Ferroptosis is a regulated form of cell death driven by the lethal accumulation of lipid peroxides in cell membranes. Several regulators of ferroptosis have been identified using cancer cell lines. However, the cellular pathways of ferroptosis in neurons remain poorly characterized. In this study, we used a mouse embryonic stem cell‐derived motor neuron model to investigate how motor neurons respond to ferroptosis inducers. Pharmacological and genetic inhibition of glutathione peroxidase 4 (GPx4) induced ferroptosis in motor neurons, while system xc− inhibition by erastin had no effect. RNA‐seq analysis showed that the expression levels of several genes were altered during RSL3‐induced ferroptosis. Subsequent bioinformatic analysis revealed alterations in several biological pathways during ferroptosis, including synaptogenesis and calcium signaling. Finally, we found that edaravone, an FDA‐approved drug for treating amyotrophic lateral sclerosis (ALS) disease, rescued motor neurons from RSL3‐induced ferroptosis. Our data highlight the crucial role of GPx4 in ferroptosis regulation and demonstrate that stem cell‐derived motor neuron culture is a valuable model to study ferroptosis at the single‐cell level in a neuronal context.