OTUD3-mediated stabilization of SLC7A11 drives sunitinib resistance by suppressing ferroptosis in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC), as the main type of RCC was treated with tyrosine kinase inhibitor (TKI) at the late stage. While drug resistance is the main challenge for TKIs like sunitinib, and the underline mechanisms remain unclear. Here, we found that OTUD3 is over-expressed in ccRCC and promotes sunitinib resistance in tumor cells. OTUD3 deubiquitinates the cystine/glutamate transporter SLC7A11 and protect it from proteasome degradation, which promotes cystine transport into cells and reduces intracellular ROS levels, thereby inhibiting sunitinib-induced ferroptosis. Our findings suggest that targeting OTUD3 could be a potential strategy to enhance ferroptosis and improve the therapeutic efficacy of sunitinib in ccRCC. • OTUD3 is correlated with prognosis and sunitinib resistant in ccRCC. • OTUD3 reduced ubiquitination of SLC7A11 to maintain its protein levels. • OTUD3 maintained protein level of SLC7A11 to prevent ferroptosis in ccRCC. • OTUD3 and SLC7A11 exhibit high expression in sunitinib resistant ccRCC.