# Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells

## TL;DR

The study finds that selenium and thioredoxin work together to protect some pancreatic cancer cells from a type of cell death called ferroptosis, suggesting a new way to treat these cancers.

## Contribution

The novel contribution is the discovery of a selenium–thioredoxin redox axis that provides ferroptosis resistance in epithelial-type pancreatic cancer cells, independent of GPX4.

## Key findings

- Epithelial-type PDAC cells resist ferroptosis via a selenium–thioredoxin axis, independent of GPX4.
- Chemical inhibition of thioredoxin reductases sensitizes epithelial cells to ferroptosis inducers.
- Selenium supplementation protects cells from ferroptosis even when glutathione is depleted.

## 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.