Evidence map›Paper›PMID 40766571›Full record

ArticlebioRxiv : the preprint server for biology2025

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

Cristina Andreani, Caterina Bartolacci, Margherita Melegari, Nicola Sargentoni, Lorenzo Luciani, Agnese Marucci, Roberta Galeazzi, Gina M DeNicola, Jessica Kilgore, Noelle Williams and 8 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Cristina AndreaniDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID 0000-0003-3245-670X
Caterina BartolacciDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID 0000-0003-2002-7721
Margherita MelegariDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID 0000-0003-3565-5560
Nicola SargentoniSchool of Science and Technology, Chemistry Division, University of Camerino, Camerino, MC, Italy.ORCID 0009-0009-2735-3440
Lorenzo LucianiSchool of Science and Technology, Chemistry Division, University of Camerino, Camerino, MC, Italy.ORCID 0000-0002-9000-7454
Agnese MarucciSchool of Biosciences and Veterinary Medicine, University of Camerino, Camerino, MC, Italy.
Roberta GaleazziDepartment of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy.ORCID 0000-0003-1792-654X
Gina M DeNicolaDepartment of Metabolism & Physiology, Moffitt Cancer Center, Tampa, FL, USA.ORCID 0000-0001-6611-6696
Jessica KilgoreDepartment of Biochemistry, University of Texas Southwestern, Dallas, TX, USA.ORCID 0000-0001-9138-2099
Noelle WilliamsDepartment of Biochemistry, University of Texas Southwestern, Dallas, TX, USA.ORCID 0000-0003-1894-5742
Stefano BertoDepartment of Neuroscience and Bioinformatics Core, Medical University of South Carolina, Charleston, SC, USA.ORCID 0000-0001-9028-9458
Massimiliano GaetaniChemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.ORCID 0000-0001-5610-0797
Prasad PattabhiDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID 0000-0002-8437-7838
Sagid S OsmanDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Ahmad T MansourDepartment of pathology, St Elizabeth hospital, Edgewood, KY, USA.
Stefania PucciarelliSchool of Biosciences and Veterinary Medicine, University of Camerino, Camerino, MC, Italy.ORCID 0000-0003-2137-5517
Rossana GalassiSchool of Science and Technology, Chemistry Division, University of Camerino, Camerino, MC, Italy.ORCID 0000-0002-8025-9615
Pier Paolo ScaglioniDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID 0000-0002-6036-5138

Funding

LCenter for Clinical and Translational Science and TrainingUL1TR001425 · NCATS · UNIVERSITY OF CINCINNATI · PI HEUBI, JAMES E., KISSELA, BRETT M · 2015 to 2024
$37.5M
The Role of Early Life Stress in Feeding BehaviorsP20GM148302 · NIGMS · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI Jose H Ledo · 2023 to 2026
$11.5M
Fatty acid metabolism regulates ferroptosis in mutant KRAS lung cancerR01CA259845 · NCI · UNIVERSITY OF CINCINNATI · PI PIER Paolo SCAGLIONI · 2022 to 2026
$2.0M
NCATS NIH HHS UL1 TR001425NCI NIH HHS R01 CA259845NIGMS NIH HHS P20 GM148302
6 · The paper itself

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.

Identifiers

PMID40766571
PMCPMC12324224

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.