Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis

Ferroptosis, distinct from necrosis, autophagy and apoptosis, is a unique form of regulated cell death，and is a potential pathogenic mechanism of neuronal loss and defunction in many neurodegenerative disorders. Recent studies have shown a presence of iron deposition in the central nervous system (CNS) of patients with multiple sclerosis (MS). However, whether ferroptosis is involved in the pathogenesis of MS remains unclear. In the present study, we tested certain classical biomarkers of ferroptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, to substantiate the relationship between ferroptosis and oligodendrocyte (OL) loss and demyelination. Our results revealed decreased levels of key molecules in glutathione antioxidant mechanisms, including system xC (xCT) and glutathione peroxidase 4 (GPX4) in spinal cord of EAE mice, with evident lipid peroxidation in OLs. Moreover, transferrin receptor and ferritinophagy further catalyzed the generation of lipid reactive oxygen species through the fenton reaction, which induced OL death and demyelination at disease peak of EAE. This phenomenon was largely reversed by administering Fer-1, an inhibitor of ferritin phagocytosis, further validating the key role of ferritin phagocytosis in EAE. Taken together, these findings demonstrate that OL loss and demyelination may be induced in EAE through, at least in part, a mechanism of ferroptosis. •Transferrin receptor and ferritinophagy induced OL death and demyelination at disease peak of EAE•Fer-1, an inhibitor of ferritin phagocytosis, suppressed the expression of MDA and 4-HNE in oligodendrocyte.•Fer-1 enhanced GPX4, xCT expression, two key molecules in glutathione antioxidant mechanisms.•Thus, ferroptosis is involved in OL loss and demyelination in EAE mice, which may be a potential therapeutic target for MS.