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

Sep 22, 2026

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Tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib are first-line options for advanced renal cell carcinoma (RCC) and lung cancer (LC), yet acquired resistance restricts durable benefit. Metabolic characterization of TKI-resistant tumors identifies ubiquitin-specific peptidase 20 (USP20) as a key driver enabling cancer cells to evade ferroptosis. USP20 upregulation binds and deubiquitinates GPX4, blocking its proteasomal degradation and sustaining antioxidant capacity. Clinically, USP20 and GPX4 co-overexpression correlates with poor prognosis. USP20 genetic loss or pharmacologic inhibition re-sensitizes resistant cells and suppresses tumor growth in vivo, revealing the USP20–GPX4 axis as a druggable vulnerability.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

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Introduction

TKI resistance and adaptive escape mechanisms

Ferroptosis as regulated cell death and GPX4 function

Deubiquitinating enzymes and therapy resistance context

Redox Biology 92 (2026) 104086 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers
Yuzhao Wang a,b,c,1, Bo Liua,b,c,1, Yanxin Zhuang a,b,c, Yulin Zhang a,b,c, Weichao Dana,b,c, Peng Ding d, Yi Wei a,b,c, Chendong Guo a,b,c, Mengxing Lia,b,c, Chi Wang a,b,c, Yelinaer Baoerbieke a,b,c, Xinqi Pei a,b,c, Lei Li a,b,c,*,
Yizeng Fan a,b,c,**
a Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
b Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China c Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, 710061, PR China
d Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi, 710038, PR China | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords: USP20
GPX4 Ferroptosis Deubiquitylation TKI resistance | | 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. | 1. Introduction Tyrosine kinase inhibitors (TKIs) have emerged as a cornerstone of targeted cancer therapy in recent decades [1,2]. However, their clinical efficacy is substantially limited by the development of acquired resistance through complex adaptive mechanisms [3–5]. This resistance arises from a repertoire of tumor escape strategies, such as secondary kinase mutations, activation of compensatory pathways, and phenotypic adaptation, that enable cancer cells to bypass the primary drug effect. While “on-target” resistance mechanisms are well-characterized, the critical role of adaptive “off-target” survival pathways, particularly those enabling evasion from TKI-induced cell death, remains an area of intense investigation and is central to overcoming the durability bottleneck in targeted therapy [6,7]. In contrast to apoptosis and autophagy, which are commonly induced by conventional chemotherapeutic agents, ferroptosis is a distinct form of regulated cell death driven by iron-dependent accumulation of lipid peroxides and by profound disruption of cellular redox homeostasis [8–10]. Owing to their hyperactive metabolic state, cancer cells often exhibit elevated intracellular iron and lipid content, predisposing them to ferroptosis initiation and propagation [11,12]. Glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, catalyzes the reduction of lipid hydroperoxides, thereby limiting peroxidative damage and suppressing ferroptotic cell death [13,14].

FAQs

How does USP20 contribute to resistance against tyrosine kinase inhibitors?

USP20 enables cancer cells to evade ferroptosis. It binds GPX4 and deubiquitinates it, preventing GPX4 proteasomal degradation and thereby maintaining antioxidant capacity.

What is the role of GPX4 in ferroptosis and therapy resistance?

GPX4 limits ferroptotic cell death by reducing lipid hydroperoxides. The document links GPX4 stability to reduced susceptibility to ferroptosis triggered by therapies.

What evidence supports targeting USP20 to overcome TKI resistance?

Genetic USP20 ablation sensitizes resistant tumors to TKI-induced ferroptosis. Pharmacological USP20 inhibition also re-sensitizes resistant tumors to sorafenib and suppresses tumor growth in vivo.

Sep 22, 2026

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