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

## TL;DR

This study shows that USP20 helps cancer cells resist tyrosine kinase inhibitors by preventing ferroptosis, offering a new approach to treat resistant kidney and lung cancers.

## Contribution

The paper identifies USP20 as a novel resistance driver that targets GPX4 to enable ferroptosis evasion in TKI-resistant cancers.

## Key findings

- USP20 deubiquitinates GPX4, preventing its degradation and promoting resistance to TKIs.
- Genetic or pharmacological inhibition of USP20 resensitizes resistant tumors to TKIs in vivo.
- USP20 and GPX4 co-overexpression in patients correlates with poor prognosis in RCC and LC.

## 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.