{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T20:45:52Z","timestamp":1786653952646,"version":"build-2736575974"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science Grant-in Aid for Scientific Research","doi-asserted-by":"publisher","award":["23K14924"],"award-info":[{"award-number":["23K14924"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K07751"],"award-info":[{"award-number":["22K07751"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K02607"],"award-info":[{"award-number":["25K02607"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Boron neutron capture therapy (BNCT) relies on the selective uptake of boron-10 compounds by tumor cells. L-boronophenylalanine (BPA) serves as a key carrier, and enhancing its accumulation is critical for improving BNCT efficacy. In this study, we examined how L-phenylalanine (Phe) restriction affects BPA uptake and related cellular responses in the tumor cell lines SAS, U87-MG, PANC-1, and A375, as well as in the immortalized keratinocyte line HaCaT. Quantitative analysis using inductively coupled plasma atomic emission spectroscopy (ICP-AES) showed that 24 h Phe restriction increased BPA uptake in the SAS, U87-MG, and PANC-1 cell lines. Colony formation assays confirmed enhanced sensitivity to neutron irradiation in these cells. RNA sequencing indicated that Phe restriction activated the integrated stress response downstream of activating transcription factor 4 (ATF4), although this pathway was not directly linked to increased BPA uptake. The LAT1\/4F2HC complex was suggested to play a predominant role in BPA transport. Liquid chromatography-tandem mass spectrometry (LC-MS\/MS) analysis showed that Phe restriction altered intracellular levels of amino acids that serve as LAT1\/4F2HC exchange substrates, suggesting a metabolic basis for enhanced BPA transport. Our results reveal that Phe restriction enhances BPA uptake and BNCT efficacy in a cell line-dependent manner, likely through the modulation of amino-acid metabolism. Therefore, targeted amino-acid manipulation prior to BNCT may represent a promising strategy to improve therapeutic outcomes.<\/jats:p>","DOI":"10.1371\/journal.pone.0355966","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T20:03:03Z","timestamp":1786651383000},"page":"e0355966","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["L-Phenylalanine restriction enhances L-boronophenylalanine uptake and improves boron neutron capture therapy efficacy in tumor cell 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