2. Academic Validation
  3. Thioredoxin Reductase 1 inhibition triggers ferroptosis in KRAS-independent lung cancers

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

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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