Mouse embryonic stem cell‐derived motor neurons are susceptible to ferroptosis

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. Ferroptosis is a form of regulated cell death driven by lipid peroxides. Here, we used mouse stem cell‐derived motor neurons to investigate which cellular pathways are altered during ferroptosis in motor neurons. We identified several biological pathways that were altered in motor neurons during RSL3‐induced ferroptosis. The results demonstrate the usefulness of the stem cell‐based model in studying neuronal ferroptosis.