Thioredoxin Reductase 1 inhibition triggers ferroptosis in KRAS-independent lung cancers

  • bioRxiv. 2025 Jul 30:2025.07.25.666783. doi: 10.1101/2025.07.25.666783.
Cristina Andreani  1 ,  Caterina Bartolacci  1 ,  Margherita Melegari  1 ,  Nicola Sargentoni  2 ,  Lorenzo Luciani  2 ,  Agnese Marucci  3 ,  Roberta Galeazzi  4 ,  Gina M DeNicola  5 ,  Jessica Kilgore  6 ,  Noelle Williams  6 ,  Stefano Berto  7 ,  Massimiliano Gaetani  8 ,  Prasad Pattabhi  1 ,  Sagid S Osman  1 ,  Ahmad T Mansour  9 ,  Stefania Pucciarelli  3 ,  Rossana Galassi  2 ,  Pier Paolo Scaglioni  1
Affiliations
  • 1. Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 2. School of Science and Technology, Chemistry Division, University of Camerino, Camerino, MC, Italy.
  • 3. School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, MC, Italy.
  • 4. Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy.
  • 5. Department of Metabolism & Physiology, Moffitt Cancer Center, Tampa, FL, USA.
  • 6. Department of Biochemistry, University of Texas Southwestern, Dallas, TX, USA.
  • 7. Department of Neuroscience and Bioinformatics Core, Medical University of South Carolina, Charleston, SC, USA.
  • 8. Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  • 9. Department of pathology, St Elizabeth hospital, Edgewood, KY, USA.
PMID: 40766571 DOI: 10.1101/2025.07.25.666783
Abstract

Lung cancers that harbor wild type KRAS (KRAS-WT) represent a molecularly diverse subset of Tumors that often lack targeted therapeutic options. Using synthesized gold(I)-based inhibitors, a multi-omics approach, and functional validation, we identified Thioredoxin reductase 1 (TXNRD1), encoding as a selective vulnerability in KRAS-WT and oncogenic KRAS mutant (KM)-independent Lung Cancer (LC). Mechanistically, TrxR1 blockade induces Ferroptosis through glutathione depletion, lipid reactive oxygen species (ROS) accumulation, and HMOX1-dependent iron overload in KRAS-WT LC both in vitro and in vivo. Furthermore, while KM LC cells are intrinsically resistant to TrxR1 inhibition, KMLC cells that acquire resistance to KRAS inhibitors (KRASi) undergo a redox shift that renders them sensitive to TrxR1 inhibition, uncovering a potential novel therapeutic vulnerability in KRASi-refractory Tumors. These findings establish TrxR1 as a targetable redox checkpoint in KRAS-WT and KRASi-resistant lung cancers and support further development of TrxR1 inhibitors.

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