Fumarate and fumarate hydratase: an immunometabolite regulator of inflammation and diseases

Once regarded solely as an intermediate of the tricarboxylic acid (TCA) cycle involved in energy production, fumarate has now emerged as a pivotal immunometabolite with far-reaching effects on inflammatory signaling and immune cell fate. This review comprehensively delineates the dual nature of fumarate, which functions as a context-dependent rheostat of inflammation. Intracellular fumarate levels are tightly regulated by enzymatic activity, transport systems, and exogenous sources, including the pharmacological agent dimethyl fumarate (DMF). Fumarate can covalently modify critical cysteine residues in proteins through a process known as succination. Importantly, DMF acts at supraphysiological concentrations and may engage mechanisms distinct from those associated with endogenously accumulated fumarate. This unique post-translational modification enables fumarate to directly modulate key signaling pathways, including nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1-alpha (HIF-1α), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, thereby orchestrating a broad anti-inflammatory program. We further examine how fumarate reshapes the functional phenotypes of macrophages, dendritic cells, T cells, and B cells, ultimately skewing immune responses toward tolerance and resolution. Crucially, this review distinguishes among the physiological roles of endogenous fumarate, the pathological consequences of fumarate accumulation resulting from fumarate hydratase (FH) deficiency, and the pharmacological actions of exogenous fumarate esters. Conversely, dysregulated fumarate metabolism, as observed in conditions such as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and systemic lupus erythematosus, can paradoxically promote pathological inflammation. The successful clinical translation of fumarate esters, particularly DMF, for the treatment of multiple sclerosis and psoriasis underscores their therapeutic potential. By synthesizing recent advances in fumarate biology, this review not only elucidates its role as a fundamental link between cellular metabolism and immunity but also highlights future directions for targeting fumarate-associated pathways in a broad spectrum of chronic inflammatory diseases.