Abstract The antioxidant glutathione (GSH) is frequently elevated in KRAS-mutant lung adenocarcinoma (LUAD), suggesting a critical role of GSH in mitigating oxidative stress and promoting tumor growth. Despite this known dependency, the role of post-translational modification of proteins with GSH (S-glutathionylation, or PSSG) in LUAD remains unclear. A redox proteome screen identified Ovarian Tumor Deubiquitinase-1 (OTUB1) as a direct target of S-glutathionylation. Crucially, we found that PSSG at Cys23 of OTUB1 acts as a regulatory switch controlling intracellular GSH levels in LUAD cell lines and organoids (Aboushousha, Science Adv. PMID: 37703360). We recently observed a significant decrease in the enzyme, glutaredoxin (GLRX), which specifically reverses PSSG, in human LUAD samples. The goal of the present study therefore was to define the role of GLRX in KrasG12D-induced tumorigenesis in vivo. KrasLSL-G12D/wt:GlrxWT/WT:ROSA26LSL-TomatoRed/WT and KrasLSL-G12D:GlrxLoxP/LoxP: ROSA26LSL-TomatoRed/WT mice received adenovirus expressing CRE recombinase (AdCRE) to induce tumor initiation and Glrx deletion or control adenovirus (AdCTR) as a control. Using In vivo imaging system (IVIS), we demonstrate that GlrxLoxP/LoxP mice had higher tumor burden at 12 weeks post-Cre administration compared to GlrxWT:WT. This was accompanied by a corresponding increase in GSH levels within the epithelial-enriched population. To further assess tumor growth, tumor organoids and precision-cut lung slices (PCLS) were established 6 weeks after AdCRE administration. Interestingly, KrasG12D:GlrxCKO organoids showed preferential growth in 3D culture compared to KrasG12D:GlrxWT-derived organoids. TomatoRed quantification, a direct indicator of tumor burden, was significantly elevated in PCLS obtained from KrasG12D:GlrxCKO mice, a phenotype that was reversed by the overexpression of Glrx. Collectively, our data established that GLRX downregulation represents a critical and previously unrecognized mechanism that LUAD cells co-opt to sense and overcome oxidative stress, thereby aggressively promoting tumor growth and survival. Funded by: R01 CA273238 Citation Format: Reem Aboushousha, Hend Abdelhamid, Maurice Newton, Janine Warren, Cuixia Erickson, Maxmilian MacPherson, Yvonne Janssen-Heininger, . Glutaredoxin-1 deficiency boosts intracellular glutathione to drive enhanced tumor survival in KRAS-mutant lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6012.
Aboushousha et al. (Fri,) studied this question.