Fumarate-based drugs protect against neuroinflammation via upregulation of anti-ferroptotic pathways.

Ferroptosis is defined as iron dependent non-apoptotic cell death. It is based on peroxidation of polyunsaturated phospholipids and subsequent membrane rupture. Lipid peroxidation is induced mainly by the hydroxyl radical, the product of the Fenton reaction between iron and hydrogen peroxide. Ferroptosis is connected to many organs and diseases including neuroinflammation. The most common inflammatory disease of the central nervous system in Western countries is multiple sclerosis leading to inflammatory demyelination and neurodegeneration. Fumarates, dimethyl fumarate (DMF) and its successor diroximel fumarate (DRF), are approved disease modifying therapies for multiple sclerosis and activate the Nrf2 pathway regulating the expression of many antioxidative enzymes. Since some of these enzymes are anti-ferroptotic, we here investigated whether the therapeutic effect of fumarates is connected to modulated sensitivity towards ferroptosis. Indeed, myelin damage induced by ferroptosis is diminished in presence of DRF or its active metabolite monomethyl fumarate. Moreover, anti-ferroptotic enzymes are upregulated in oligodendrocytes upon DRF treatment as well as in cerebellum of DMF-treated mice and in peripheral blood mononuclear cells of patients receiving DMF. This effect is absent in primary fibroblasts derived from osteo- or rheumatoid arthritis patients. In summary, our data offer a new organ- and disease-specific molecular anti-inflammatory mechanism of DRF.