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[This article belongs to Volume - 70, Issue - 3]
Published on : 2025-03-20 14:17:21
Article Code: AMJ-20-03-2025-12315
Title : Ferroptosis Induction via Glutathione Peroxidase 4 Inhibition Sensitizes Pancreatic Cancer Stem Cells to Radiotherapy
Author(s) : Dr. Omar Khalid, Dr. Sarah O'Brien
Abstract :
Pancreatic ductal adenocarcinoma (PDAC) stem cells (CSCs) exhibit intrinsic radioresistance driven by robust
antioxidant defenses. We demonstrate that CSCs isolated from patient-derived xenografts exhibit elevated
glutathione (GSH) synthesis and GPX4 expression, rendering them resistant to lipid peroxidation. Pharmacological
inhibition of GPX4 using RSL3 or genetic knockdown induced ferroptosis selectively in CSCs while sparing
differentiated tumor cells. Combination of GPX4 inhibition with stereotactic body radiation therapy (SBRT) eradicated
CSC pools, prevented tumor relapse, and prolonged survival in immunocompromised mice. RNA-seq analysis
revealed downregulation of SLC7A11 and activation of ACSL4 as molecular determinants of ferroptotic susceptibility.