{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUridine‐cytidine kinase 2 (UCK2) is a pivotal enzyme in the pyrimidine salvage pathway that catalyzes the phosphorylation of uridine and cytidine, a reaction that is essential not only for normal nucleotide metabolism but also for the activation of several cytotoxic pyrimidine analogues. Genetic variation in the UCK2 gene has been linked to an increased risk of testicular germ cell tumors, while chromosomal rearrangements leading to its overexpression have been identified in lymphoid malignancies. In addition, UCK2 is responsible for activating novel antitumor agents such as 3′‐ethynyl nucleosides, underscoring its dual role in both tumorigenesis and chemotherapy response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUCK2 overexpression has been documented across a wide array of cancers. In lung cancer, high UCK2 levels are detectable even at the early stages and correlate with advanced T and N stages, early recurrence, and poor overall patient survival. Similarly, studies in neuroblastoma demonstrate that elevated UCK2 enhances the phosphorylation of ribonucleosides and increases the cytotoxicity of chemotherapeutic agents, while in hepatocellular carcinoma (HCC) its upregulation is associated with both aggressive tumor behavior and reduced survival. Moreover, investigation into novel cytidine analogues (e.g. RX‑3117) has revealed that UCK2 is the primary enzyme responsible for their activation. Although certain Epstein–Barr virus–related studies have outlined the process of lymphoid transformation, a direct role for UCK2 in these contexts has not been established."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic evaluations of UCK2 have revealed that its catalytic phosphate transfer from ATP to the 5′‐hydroxyl group of nucleosides proceeds by a concerted mechanism that involves simultaneous formation and breakage of P–O bonds and proton abstraction by a conserved active site residue. This superior kinetic efficiency compared with its paralog UCK1 underscores UCK2’s key role in regulating pyrimidine metabolism. Such mechanistic insights have fueled the design of UCK2‐dependent prodrugs and positron emission tomography (PET) probes, while its overexpression in malignancies further positions UCK2 as a promising diagnostic biomarker and therapeutic target for cancers including metastatic HCC."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fredrick R Schumacher, Zhaoming Wang, Rolf I Skotheim, et al. 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