Dimethyl fumarate as a versatile therapeutic agent: molecular mechanisms and potential clinical applications

Abstract Dimethyl fumarate (DMF) is an electrophilic compound used clinically for multiple sclerosis and psoriasis. We elaborate here that the pharmacological effects of DMF extend beyond the well-known activation of the NRF2 antioxidative pathway. Indeed, DMF directly modifies reactive cysteine residues on multiple proteins in immune and neural cells, leading to diverse anti-inflammatory, immunomodulatory, and neuroprotective actions. Recent studies revealed that DMF may affect proteins involved in inflammasome activation, glycolysis, and cell signaling pathways, including JAK-STAT and NF-kB. These effects may expand the potential clinical applications of DMF in diverse pathologies, including neurodegenerative, cardiovascular, and pulmonary diseases. We summarize current findings on chemical reactivity, target proteins, and emerging clinical applications of DMF, highlighting new opportunities for DMF repurposing.