The Deubiquitylase USP52 Regulates Cell Proliferation and Ferroptosis through Stabilizing SLC7A11/xCT in Bladder Cancer

Ferroptosis, a recently coined non-apoptotic form of cell death, is triggered by lethal accumulation of iron-dependent lipid peroxidation. SLC7A11/xCT, acts as a central hub in ferroptosis, is closely related to the development of multiple human diseases. However, the specific functions and potential regulatory mechanisms of ferroptosis, especially xCT protein, in bladder cancer (BLCA) remain poorly understood. Herein, through an unbiased siRNA screen targeting 96 deubiquitinases (DUBs), we identified USP52/PAN2 as a top regulator essential for xCT protein translational activity and ferroptosis process. Functionally, loss of USP52 inhibits glutathione (GSH) synthesis through xCT degradation, leading to elevated lipid peroxidation and ferroptosis, thereby suppresses BLCA progression. Mechanistically, USP52 physically interacts with xCT through its WD40 domain, biochemically hydrolyzes the K48-conjugated ubiquitin chains of xCT at K4 and K12, thereby promotes its protein stability. Importantly, USP52 expression demonstrates a positive correlation with xCT expression in clinical BLCA samples, and high USP52 expression is linked to a worse progression and prognosis. Additionally, USP52 depletion and IKE synergistically restrained the progression of BLCA by triggering ferroptosis in vivo. Collectively, our findings reveal a molecular mechanism of USP52-xCT axis in ferroptosis, and uncover a previously unappreciated role of USP52 in BLCA tumorigenesis.