{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUridine phosphorylase 1 (UPP1), a central enzyme in the pyrimidine salvage pathway, catalyzes the reversible phosphorolysis of uridine into uracil and ribose‐1‐phosphate. This activity is critical not only for regulating intracellular uridine levels but also for the bioactivation of fluoropyrimidine pro‐drugs such as 5‑fluorouracil and capecitabine. Its expression is tightly controlled at the transcriptional level—including regulation by factors such as the tumor suppressor p53 and basic fibroblast growth factor—and its structure dynamically adapts during substrate binding, with high ATP levels even capable of destabilizing its folded conformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a number of human malignancies, UPP1 is overexpressed and appears to act as an oncogene. For example, elevated UPP1 levels in breast cancer have been associated with poorer patient survival, while in thyroid tumors UPP1 upregulation correlates with increased tumor size, lymph node metastasis, and enhanced epithelial-to-mesenchymal transition. Similarly, in glioma, high UPP1 expression marks the mesenchymal subtype and is linked with an immunosuppressive tumor microenvironment—as evidenced by increased cytokine release and immune checkpoint (e.g., PD‑L1) expression—as well as with worse overall survival. Moreover, in lung adenocarcinoma, tumor subpopulations expressing high levels of UPP1 are found at the invasive front and are implicated in dampening local anti-tumor immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUPP1’s expression and function are further modulated by diverse regulatory mechanisms that extend its influence beyond classic oncogenesis. Differential transcriptional responses to active vitamin D in colon tissues suggest that genetic regulatory variants may impact UPP1 expression among distinct populations, potentially contributing to colorectal cancer risk. In osteo-lineage cells, basic fibroblast growth factor markedly increases UPP1 transcription, thereby modulating sensitivity to 5‑fluorouracil-induced apoptosis. In addition, in inflammatory diseases such as psoriasis, UPP1 is activated by the IL‑6/STAT3 pathway to enhance glycolysis and promote keratinocyte proliferation and cell-cycle progression, thereby contributing to disease pathogenesis. Finally, analyses in blood cell populations have detailed its substrate specificity as well as its distinct roles in nucleoside metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Giuseppe Pizzorno, Deliang Cao, Janine J Leffert, et al. 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