Document resource
Fumarate derivatives are FDA-approved molecules used to treat autoimmune diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant enzyme expression. However, their effects on human cardiomyocytes remain unclear. We investigated whether the fumarate derivatives dimethyl fumarate (DMF), monomethyl fumarate (MMF), and diroximel fumarate (Vm) enhance antioxidant defences and modulate metabolism in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM).DMF significantly increased Nrf2 nuclear translocation by 29%, as shown by subcellular fractionation. DMF, MMF, and Vm upregulated antioxidant genes, including NQO1, TXNRD1, HMOX1, and SRXN1, in a dose- and time-dependent manner. Transcriptomic analysis of DMF- treated hiPSC-CM revealed significant upregulation of antioxidant genes and identified Nrf2 as a top-enriched transcription factor. DMF also activated additional antioxidant pathways, including glutathione metabolism, the pentose phosphate pathway, and NADPH regeneration. Furthermore, DMF downregulated inflammatory signalling pathways, supporting its immunoregulatory role.Sulforaphane, a known Nrf2 activator, induced similar antioxidant gene expression changes. A genetic mouse model with constitutive cardiac Nrf2 activation further confirmed that Nrf2 mediates these antioxidant and immune-adaptive effects.Given the link between oxidative and metabolic processes, we also assessed metabolic changes. DMF, MMF, and Vm reprogrammed cardiomyocyte metabolism by reducing fatty acid oxidation and increasing glycolysis, as shown by qPCR and radioactive metabolic flux assays. These changes were accompanied by transient mitochondrial fragmentation and reduced oxygen consumption, suggesting a shift from oxidative to glycolytic metabolism.In conclusion, fumarate derivatives activate key Nrf2-dependent antioxidant pathways and reveal a novel role in regulating human cardiomyocyte metabolism.