Fumarate and Its Esters: Physiology, Pathology, Molecular Mechanisms, Diseases, and Therapy.

Fumarate is a critical intermediate of the tricarboxylic acid cycle that, beyond its metabolic role, has emerged as an important regulator of cellular signaling. Fumaric acid esters (FAEs), including dimethyl fumarate and monomethyl fumarate, have been utilized as therapeutic agents for immune-mediated diseases and are being explored for broader applications. Accumulating evidence indicates that both fumarate and FAEs modulate diverse biological processes through mechanisms such as protein succination and metabolic reprogramming. In this review, we discuss the current understanding of fumarate and FAEs in health and disease, integrating evidence from various clinical and preclinical research. We conclude that protein succination represents an important mechanism for many of their biological activities, whereas differences in electrophilicity, cell permeability, intracellular distribution, and the metabolic context dictate distinct molecular targets and functional outcomes. We further evaluate the opportunities and limitations of current research, highlighting key technical challenges that complicate mechanistic interpretation and clinical translation. By bridging and differentiating the biology of endogenous fumarate and the pharmacology of FAEs, this review provides a conceptual framework for interpreting existing studies and outlines future directions for developing more precise fumarate-targeted interventions in diseases.