{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe SLC29A1 gene encodes the human equilibrative nucleoside transporter 1 (hENT1), a widely expressed membrane protein responsible for the bidirectional, concentration‐dependent transport of natural nucleosides as well as nucleoside analog drugs. Structural and mutagenesis studies have identified critical transmembrane domains and specific amino acid residues that determine substrate binding, transport activity, and even sensitivity to inhibitors such as dipyridamole. hENT1 not only mediates the cellular uptake of chemotherapeutic agents such as gemcitabine, cytarabine, and ribavirin but is also found in unexpected locations like the mitochondrial membrane—thereby influencing drug toxicity and efficacy. Moreover, reduced hENT1 expression has been linked to treatment resistance in malignancies including pancreatic ductal adenocarcinoma and acute myeloid leukemia, while genetic variations in SLC29A1 modulate both transporter function and clinical chemosensitivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its core function in nucleoside transport, hENT1 exhibits notable tissue‐specific localization and regulation that profoundly affect both normal physiology and pharmacological outcomes. In polarized epithelial cells such as those of the kidney, liver, and placenta, hENT1 is sorted to specific membrane domains to coordinate vectorial transport. Regulatory mechanisms—including promoter polymorphisms, post‐transcriptional modifications, and responses to metabolic stress—modulate hENT1 expression and, consequently, extracellular adenosine levels. These factors have been shown to influence treatment responses across various diseases, with hENT1 expression levels serving as predictive biomarkers for gemcitabine and ribavirin efficacy in cancer and viral disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further expands the role of SLC29A1 beyond conventional nucleoside transport. Novel findings have implicated mutations in SLC29A1 as the genetic basis for the Augustine blood group system—with attendant effects on bone mineral homeostasis—and have linked aberrant hENT1 activity to neurodegenerative disorders such as Huntington's disease. Moreover, pharmacologic modulation of hENT1 by agents like ticagrelor and verapamil, as well as its interplay with metabolic pathways (including glycolysis), provides promising strategies to overcome chemoresistance and improve outcomes in solid tumors. Collectively, these studies underscore hENT1 as a pivotal determinant not only in drug uptake and disposition but also in cellular adaptation to metabolic and ischemic stresses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dhruba J SenGupta, Pek Y Lum, Yurong Lai, et al. 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