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<p>Fumarate is increasingly recognized as a metabolic signal with dual effects in cardiovascular disease. Pharmacologic doses of dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) transiently activate Nrf2 and HCAR2 pathways, offering antioxidant, anti-inflammatory, and antifibrotic benefits. These include reduced endothelial activation, macrophage foam cell formation, and vascular remodeling in atherosclerosis, ischemia–reperfusion injury, hypertension, and diabetic cardiomyopathy. In contrast, sustained fumarate accumulation—due to fumarate hydratase 1 (FH1) loss—drives protein succination, cGAS–STING activation, HIF-1α stabilization, and epigenetic enzyme inhibition, promoting oxidative stress, inflammation, and cellular senescence. FH1 insufficiency is associated with plaque destabilization, renal dysfunction, and galectin-3–driven fibrosis. Despite promising preclinical results, human data remain limited: FH1 mutation syndromes rarely present with cardiovascular phenotypes, and DMF clinical trials have not evaluated major cardiovascular endpoints. Future studies should define a therapeutic window, develop succination biomarkers, and assess long-term effects to safely harness fumarate’s hormetic potential in cardiovascular medicine.</p> Graphical Abstract <p></p>

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Fumarate Signaling in Cardiovascular Disease: Therapeutic Potential and Pathologic Pitfalls of DMF/MMF and FH1 Deficiency

  • 期刊论文

  • 发表日期：

    2025年9月23日

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  • Xi-Long Zheng,
  • Hao Yin

摘要

Fumarate is increasingly recognized as a metabolic signal with dual effects in cardiovascular disease. Pharmacologic doses of dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) transiently activate Nrf2 and HCAR2 pathways, offering antioxidant, anti-inflammatory, and antifibrotic benefits. These include reduced endothelial activation, macrophage foam cell formation, and vascular remodeling in atherosclerosis, ischemia–reperfusion injury, hypertension, and diabetic cardiomyopathy. In contrast, sustained fumarate accumulation—due to fumarate hydratase 1 (FH1) loss—drives protein succination, cGAS–STING activation, HIF-1α stabilization, and epigenetic enzyme inhibition, promoting oxidative stress, inflammation, and cellular senescence. FH1 insufficiency is associated with plaque destabilization, renal dysfunction, and galectin-3–driven fibrosis. Despite promising preclinical results, human data remain limited: FH1 mutation syndromes rarely present with cardiovascular phenotypes, and DMF clinical trials have not evaluated major cardiovascular endpoints. Future studies should define a therapeutic window, develop succination biomarkers, and assess long-term effects to safely harness fumarate’s hormetic potential in cardiovascular medicine.

Graphical Abstract