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Accurate quantification of cystine levels is therefore essential for assessing lysosomal transport deficiency and treatment response. In vitro cell models provide a controlled platform to investigate disease mechanisms and to evaluate emerging therapeutic strategies. To determine intracellular cystine concentrations in these models, adequate sample preparation, storage, and highly sensitive analytical methods are essential. In this work, a rapid hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS\/MS) method was developed for the direct determination of cystine in cellular extracts. Use of a PEEK-lined HILIC-Z column proved essential to minimize metal-induced peak tailing and improve chromatographic performance. The total run time of 5\u00a0min enabled high-throughput analysis, facilitating efficient screening of novel therapeutic approaches in cellular systems. Validation demonstrated excellent linearity (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009\u2265\u20090.9986) and a lower limit of quantification (LLOQ) of 12.5\u00a0nM, representing a\u2009&gt;\u20098-fold improvement over reported reversed-phase LC methods. Addition of N-ethylmaleimide (NEM) prior to cell lysis effectively limited cysteine oxidation and maintained sample stability at 4\u00a0\u00b0C. Applicability was demonstrated in an isogenic laboratory HEK293T cell model, where\n                    <jats:italic>CTNS<\/jats:italic>\n                    -knockout (KO) cells exhibited significantly elevated intracellular cystine levels compared to wild-type (WT) cells. As additional controls, elevated levels were successfully restored following cysteamine treatment or lentiviral-vector (LV)-mediated CTNS protein re-expression. The developed method hence provides a sensitive and reliable analytical platform for in vitro evaluation of novel therapeutic strategies in cystinosis research.\n                  <\/jats:p>","DOI":"10.1007\/s00216-026-06526-x","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:27:29Z","timestamp":1777526849000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the quantification of intracellular cystine and its application in cystinosis research"],"prefix":"10.1007","author":[{"given":"Toon","family":"Verdonck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger Mora","family":"de la Serna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Augustijns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Gijsbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5502-5801","authenticated-orcid":false,"given":"Deirdre","family":"Cabooter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"issue":"12","key":"6526_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10123539","volume":"10","author":"A Reda","year":"2021","unstructured":"Reda A, Veys K, Besouw M. 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