Fumarate hydratase (FH) is a metabolic enzyme that catalyzes the dehydration of L-malate to fumarate, functioning in both cytosolic and mitochondrial compartments [UniProt]. FH plays dual roles in cellular metabolism and DNA repair. In metabolism, it participates in the tricarboxylic acid cycle, urea cycle, and arginine catabolism as a by-product of amino acid breakdown. In DNA repair, FH translocates to the nucleus following DNA damage and phosphorylation by PRKDC, accumulating at double-strand breaks where it catalyzes fumarate formation 1. This fumarate inhibits KDM2B histone demethylase activity, enhancing H3K36me2 dimethylation and promoting non-homologous end-joining 1. FH mutations impair this dual functionality. Loss-of-function FH mutations cause fumarate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases including histone demethylases and TET family hydroxylases, leading to genome-wide alterations in histone and DNA methylation that contribute to tumorigenesis 2. Clinically, FH deficiency presents as an autosomal recessive metabolic disorder and hereditary leiomyomatosis with renal cell carcinoma, where FH-deficient RCC represents a distinct cancer subtype 3. AKR1B10 and s-2-succinocysteine serve as diagnostic biomarkers for FH-deficient RCC, with AKR1B10 demonstrating 100% sensitivity and 91.4% specificity 3.