ArticleOncogene2026
USP7-mediated deubiquitination of the KEAP1-NRF2-HMOX1 axis enhances radioresistance in non-small cell lung cancer by suppressing ferroptosis.
Article in Oncogene, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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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.
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.
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Who cites it
1 citing paper in PubMed.
- OTUD5 promotes AML progression by stabilizing SLC7A11 to suppress ferroptosis.Cell cycle (Georgetown, Tex.) · 2026Article
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Authors and funding
4 authors.
Funding
Abstract
Radioresistance remains the primary cause of radiotherapy failure in non-small cell lung cancer (NSCLC). This study investigated the regulatory role of HMOX1-mediated ferroptosis in NSCLC radiosensitivity. Radioresistant cell models (H1650R/H1975R) were established through fractionated irradiation of parental H1650/H1975 cells. Transcriptomic analysis by RNA sequencing revealed significant HMOX1 suppression in resistant cells. Functional validation demonstrated that HMOX1 overexpression enhanced radiation sensitivity via ferroptosis induction, whereas HMOX1 knockdown aggravated radioresistance. Mechanistic investigations identified USP7 as a key deubiquitinating enzyme that stabilizes KEAP1 through K48-linked polyubiquitin chain cleavage, thereby promoting NRF2 ubiquitination and suppressing HMOX1 transcription. Pharmacological inhibition using KI696 blocked KEAP1-NRF2 interaction, restoring HMOX1 expression. Notably, the USP7 inhibitor GNE-6640 destabilized KEAP1, upregulated NRF2/HMOX1 axis activity, and triggered ferroptosis in resistant cells. In vivo studies confirmed that GNE-6640 synergized with radiotherapy to suppress tumor growth and pulmonary metastasis in xenograft and NSG mouse models, as monitored by bioluminescence imaging. These findings establish the USP7-KEAP1-NRF2-HMOX1 axis as a critical determinant of radioresistance, demonstrating that targeted USP7 inhibition with GNE-6640 reactivates ferroptosis and restores radiosensitivity. This dual-mechanistic approach provides a novel therapeutic strategy to overcome treatment resistance in NSCLC.
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Registered trials
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