USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers

  • Redox Biol. 2026 May:92:104086. doi: 10.1016/j.redox.2026.104086.
Yuzhao Wang  1 ,  Bo Liu  1 ,  Yanxin Zhuang  1 ,  Yulin Zhang  1 ,  Weichao Dan  1 ,  Peng Ding  2 ,  Yi Wei  1 ,  Chendong Guo  1 ,  Mengxing Li  1 ,  Chi Wang  1 ,  Yelinaer Baoerbieke  1 ,  Xinqi Pei  1 ,  Lei Li  3 ,  Yizeng Fan  4
Affiliations
  • 1. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, PR China.
  • 2. Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi, 710038, PR China.
  • 3. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, PR China. Electronic address: [email protected].
  • 4. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, PR China. Electronic address: [email protected].
PMID: 41844497 DOI: 10.1016/j.redox.2026.104086
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.

Keywords
Deubiquitylation; Ferroptosis; GPX4; TKI resistance; USP20.
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