{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC6A14 is a sodium‐ and chloride‐dependent transporter with a broad substrate specificity that mediates the uptake of both neutral and basic amino acids—including arginine, leucine, and even non‐α amino acids like β‐alanine—thereby contributing to the absorption of essential nutrients. Structural and functional studies have identified key features of this transporter, with molecular modeling approaches shedding light on critical residues involved in substrate recognition and translocation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cystic fibrosis, genetic association studies have implicated SLC6A14 as a modifier gene. In epithelial cells of the respiratory tract, SLC6A14 facilitates the uptake of l‑arginine from the airway surface liquid—a process shown to be up‐regulated upon bacterial flagellin exposure—which in turn can diminish the extracellular arginine pool that promotes Pseudomonas aeruginosa attachment. These findings, together with advanced colocalization analyses, underscore the role of SLC6A14 in modulating airway host defense and influencing disease variability among CF patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nElevated expression of SLC6A14 has also been observed in several cancers, where its overactivity supports the increased amino acid demands of rapidly proliferating tumor cells. In colorectal cancer, for example, marked up‐regulation of SLC6A14 correlates with increased arginine uptake and altered nitric oxide synthesis. Similarly, in endocrine therapy–resistant breast cancers, pancreatic ductal adenocarcinoma, and gastric cancer, SLC6A14 overexpression enhances malignant phenotypes by promoting proliferative, migratory, and epithelial-to-mesenchymal transition programs—mechanisms that are being actively explored as potential targets for diagnostic imaging and therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in CF and cancer, SLC6A14 has been linked to metabolic regulation and obesity. Genome‐wide association studies in different populations have identified polymorphisms in the SLC6A14 gene that are associated with excess adiposity, potentially through the modulation of tryptophan availability and subsequent serotonin synthesis—a key pathway in appetite regulation and energy balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn inflammatory conditions such as ulcerative colitis, increased SLC6A14 expression has been observed and linked to disease pathogenesis. Enhanced expression appears to facilitate ferroptosis—a regulated form of cell death—through a mechanism involving C/EBPβ-mediated repression of PAK6. Transcriptomic analyses further suggest that dysregulation of SLC6A14, along with other mucosal transcripts, may contribute to the inflammatory milieu seen in ulcerative colitis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have examined the role of SLC6A14 in other pathophysiological contexts. Studies exploring its genetic variants have even suggested a potential link with male infertility, while emerging evidence continues to unveil its broad clinical relevance across diverse conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elina Suviolahti, Laura J Oksanen, Miina Ohman, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "SLAS Discov (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/2472555219867317"}], "href": "https://doi.org/10.1177/2472555219867317"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31373846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31373846"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lei Sun, Johanna M Rommens, Harriet Corvol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2221"}], "href": "https://doi.org/10.1038/ng.2221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22466613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22466613"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Michelle Di Paola, Amber J Park, Saumel Ahmadi, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "SLC6A14"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Is a Genetic Modifier of Cystic Fibrosis That Regulates "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Pseudomonas aeruginosa"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Attachment to Human Bronchial Epithelial Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mBio.02073-17"}], "href": "https://doi.org/10.1128/mBio.02073-17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29259090"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29259090"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "M Ruffin, J Mercier, C Calmel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[SLC6A14, a modifier gene in cystic fibrosis]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Rev Mal Respir (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.rmr.2020.02.008"}], "href": "https://doi.org/10.1016/j.rmr.2020.02.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32146055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32146055"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Fan Wang, Naim Panjwani, Cheng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A flexible summary statistics-based colocalization method with application to the mucin cystic fibrosis lung disease modifier locus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2021.12.012"}], "href": "https://doi.org/10.1016/j.ajhg.2021.12.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35065708"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35065708"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Naren Gupta, Seiji Miyauchi, Robert G Martindale, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of the amino acid transporter ATB0,+ (SLC6A14) in colorectal cancer and metastasis in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2005.04.002"}], "href": "https://doi.org/10.1016/j.bbadis.2005.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15905073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15905073"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Marina Bacci, Nicla Lorito, Luigi Ippolito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reprogramming of Amino Acid Transporters to Support Aspartate and Glutamate Dependency Sustains Endocrine Resistance in Breast Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2019.06.010"}], "href": "https://doi.org/10.1016/j.celrep.2019.06.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31269432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31269432"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Alan R Penheiter, Sibel Erdogan, Stephen J Murphy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptomic and Immunohistochemical Profiling of SLC6A14 in Pancreatic Ductal Adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2015/593572"}], "href": "https://doi.org/10.1155/2015/593572"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26106611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26106611"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "V Coothankandaswamy, S Cao, Y Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Pharmacol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bph.13616"}], "href": "https://doi.org/10.1111/bph.13616"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27747870"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27747870"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Qie Guo, Wen Xu, Xiao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SLC6A14 Depletion Contributes to Amino Acid Starvation to Suppress EMT-Induced Metastasis in Gastric Cancer by Perturbing the PI3K/AKT/mTORC1 Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/7850658"}], "href": "https://doi.org/10.1155/2022/7850658"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35865664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35865664"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Cunshu Dang, Quan Bian, Fengbiao Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Machine learning identifies SLC6A14 as a novel biomarker promoting the proliferation and metastasis of pancreatic cancer via Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-024-52646-8"}], "href": "https://doi.org/10.1038/s41598-024-52646-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38267509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38267509"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Emmanuelle Durand, Philippe Boutin, David Meyre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/diabetes.53.9.2483"}], "href": "https://doi.org/10.2337/diabetes.53.9.2483"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15331564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15331564"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Raquel C K Miranda, Silvia B Vetter, Júlia P Genro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SLC6A14 and 5-HTR2C polymorphisms are associated with food intake and nutritional status in children."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Biochem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clinbiochem.2015.07.003"}], "href": "https://doi.org/10.1016/j.clinbiochem.2015.07.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26160208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26160208"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Anders Eriksson, Carl-Fredrik Flach, Anders Lindgren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Five mucosal transcripts of interest in ulcerative colitis identified by quantitative real-time PCR: a prospective study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Gastroenterol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-230X-8-34"}], "href": "https://doi.org/10.1186/1471-230X-8-34"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18700007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18700007"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yanjun Chen, Wenying Yan, Yuqi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPβ-PAK6 axis in ulcerative colitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-022-04594-7"}], "href": "https://doi.org/10.1007/s00018-022-04594-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36272033"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36272033"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Qing Gu, Huan Xia, Yue-Qiong Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v30.i3.252"}], "href": "https://doi.org/10.3748/wjg.v30.i3.252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38314135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38314135"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Elham Siasi, Ahmad Aleyasin "}, {"type": "b", "children": [{"type": "t", "text": "Four Single Nucleotide Polymorphisms in INSR, SLC6A14, TAS2R38, and OR2W3 Genes in Association with Idiopathic Infertility in Persian Men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Reprod Med (2016)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27172637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27172637"}]}]}]}