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Andreani C, Bartolacci C, Melegari M, Sargentoni N, Luciani L, Marucci A, Galeazzi R, DeNicola GM, Kilgore J, Williams N, Berto S, Gaetani M, Pattabhi P, Osman SS, Mansour AT, Pucciarelli S, Galassi R, Scaglioni PP
bioRxiv - (-) - [2025-07-30; online 2025-07-30]
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.
Chemical Proteomics [Collaborative]
PubMed 40766571
DOI 10.1101/2025.07.25.666783
Crossref 10.1101/2025.07.25.666783
pmc: PMC12324224
pii: 2025.07.25.666783
figshare: 10.25452/figshare.plus.24667905.v2