ArticleRedox biology2026
USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers.
Article in Redox biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Beyond angiogenesis: integrating ferroptosis and metabolic rewiring for next-generation RCC therapy.Frontiers in oncology · 2026Review
- Mitochondrial Dysfunction in Renal Cell Carcinoma: A Comprehensive Review of Pathogenic Mechanisms and Emerging Therapeutic Opportunities.Oncology research · 2026Review
Corrections and comments
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tyrosine kinase inhibitors (TKIs) including sunitinib and sorafenib remain first-line therapies for advanced renal cell carcinoma (RCC) and lung cancer (LC), but their efficacy is limited by acquired resistance. By characterizing metabolic adaptations in TKI-resistant tumors, we identify ubiquitin-specific peptidase 20 (USP20) as a critical resistance driver that enables cancer cells to evade ferroptosis. We demonstrate TKI-resistant cells upregulate USP20, which binds and deubiquitinates the ferroptosis suppressor GPX4, preventing its proteasomal degradation. Clinically, USP20 and GPX4 are co-overexpressed in RCC and LC patients, correlating with poor prognosis. Mechanistically, USP20 removes K48-linked polyubiquitination on GPX4, sustaining cellular antioxidant capacity. Genetic USP20 ablation sensitizes resistant tumors to TKI-induced ferroptosis. Pharmacological inhibition of USP20 was found to resensitize TKI-resistant tumors to sorafenib, resulting in marked suppression of tumor growth in vivo. Our work uncovers the USP20-GPX4 axis as a druggable linchpin of TKI resistance, revealing ferroptosis evasion as a metabolic vulnerability and proposing a new therapeutic paradigm for overcoming TKI tolerance in RCC and LC.
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Registered trials
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