Document Type

Article

Publication Date

2-22-2026

Department

Department of Biological Sciences

Abstract

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− 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’s 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–thioredoxin 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.

Publisher's Statement

© 2026 by the authors. Licensee MDPI, Basel, Switzerland. Publisher’s version of record: https://doi.org/10.3390/ijms27042062

Publication Title

International Journal of Molecular Sciences

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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