{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC28A1, which encodes human concentrative nucleoside transporter‐1 (hCNT1), functions as a high‐affinity, sodium‐coupled transporter that selectively mediates the uptake of pyrimidine nucleosides. By coupling Na⁺ gradients to nucleoside transport, hCNT1 facilitates the cellular entry of both naturally occurring substrates and nucleoside analog chemotherapeutics—such as gemcitabine and 5‑azacytidine—thus playing a pivotal role in drug disposition. In many polarized epithelial cells, hCNT1 is targeted predominantly to the apical membrane, a localization that enables directional transport critical for both nucleoside salvage and effective drug delivery."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in hCNT1 expression or membrane targeting have been frequently linked to chemoresistance in several human cancers, including pancreatic, ovarian, and breast carcinomas. Reduced or mislocalized hCNT1 can lead to decreased uptake of nucleoside analogs, thereby limiting drug cytotoxicity and contributing to poor clinical outcomes. Moreover, several studies have identified single nucleotide polymorphisms in the SLC28A1 gene that modulate drug bioavailability and toxicity, suggesting that hCNT1 status may serve as a useful predictive marker for treatment response. Intriguingly, experimental restoration of hCNT1 expression not only reestablishes effective drug transport but also appears to trigger transceptor-like signaling events that affect cell-cycle progression and promote tumor cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "10", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, detailed mutagenesis and structural studies have illuminated key domains and conserved residues within hCNT1 that are essential for its transport activity, membrane expression, and ion coupling. Specific amino acid substitutions within transmembrane segments have been shown to alter substrate selectivity or even uncouple nucleoside transport from Na⁺ movement, underscoring the fine-tuned mechanisms governing function. 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