Xanthine dehydrogenase (XDH) is a rate-limiting enzyme in purine catabolism that catalyzes the sequential oxidation of hypoxanthine to xanthine and then to uric acid 1. As part of the xanthine oxidoreductase (XOR) enzyme complex, XDH functions primarily through NAD+-dependent oxidation, distinguishing it from the oxygen-dependent xanthine oxidase form 2. Beyond purine metabolism, XDH contributes to reactive oxygen species generation and participates in nitrite reduction and other metabolic processes 1. XDH plays important roles in both physiological and pathological contexts. In hepatocellular carcinoma, XDH loss in tumor-associated macrophages promotes immunosuppressive M2 polarization through the XOR-IDH3α axis, enhancing CD8+ T-cell exhaustion 3. In intrahepatic cholangiocarcinoma, elevated XDH supports EGFR tyrosine kinase inhibitor resistance by promoting EGFR stability and DNA damage repair 4. Additionally, fatty acid oxidation-induced HIF-1α activation upregulates XDH to facilitate hepatic urate synthesis in dyslipidemia-associated hyperuricemia 5. Clinically, XDH dysfunction causes xanthinuria type 1, a rare metabolic disorder. XDH inhibition via drugs like allopurinol is the primary treatment for gout and hyperuricemia 2. Genetic variants in XDH (rs2295475) interact with NUDT15 polymorphisms to predict azathioprine-induced leukopenia risk 6, highlighting pharmacogenetic relevance.