{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:28:52Z","timestamp":1772087332738,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R15CA246336-01"],"award-info":[{"award-number":["1R15CA246336-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc\u2212 inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Sepp1 knockdown does not alter sensitivity, indicating that selenium\u2019s protective effect is independent of Sepp1. Instead, epithelial-type cells rely on both cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) to maintain ferroptosis resistance. Chemical inhibition of thioredoxin reductases abolishes selenium-mediated protection and sensitizes epithelial cells to ferroptosis inducers, while dual genetic suppression of TrxR1 and TrxR2 similarly restores ferroptosis sensitivity. These findings uncover a selenium\u2013thioredoxin redox axis that functions independently of GPX4 and contributes ferroptosis resistance in epithelial-type PDAC cells. Co-targeting cysteine metabolism and thioredoxin reductases may therefore represent a rational strategy to overcome ferroptosis resistance in some PDAC subtypes.<\/jats:p>","DOI":"10.3390\/ijms27042062","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:00:52Z","timestamp":1771840852000},"page":"2062","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Arslan","family":"Amer","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4801-2882","authenticated-orcid":false,"given":"Micah","family":"Idowu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aqsa","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa","family":"Abbas","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tahiyat","family":"Alothaim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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