2. Academic Validation
  3. USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers

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

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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