PSMD8 cooperates with USP14 to promote bladder cancer progression by inhibiting ferroptosis.

The ubiquitin-proteasome system (UPS) is crucial for regulating protein stability and essential cellular functions, including cell survival and proliferation. Dysregulation of UPS components contributes directly to malignant tumor development. This study investigates the significance of the proteasome subunit PSMD8 in bladder cancer (BLCA) pathogenesis. We found that elevated PSMD8 expression in BLCA specimens is strongly associated with a worse patient prognosis. Mechanistic studies demonstrated that PSMD8 promotes BLCA cell proliferation, migration, and carcinogenesis. PSMD8 negatively regulates ferroptosis, but not apoptosis, by directly interacting with and stabilizing SLC7A11, a known ferroptosis suppressor. Furthermore, we illustrate that ubiquitin-specific peptidase 14 (USP14) collaborates with PSMD8 to enhance SLC7A11 protein abundance. Reduction of PSMD8, SLC7A11, or USP14 sensitizes BLCA cells to cisplatin. Our findings demonstrate that the PSMD8/USP14 axis stabilizes SLC7A11 to suppress ferroptosis, promoting malignant growth, which suggests that targeting SLC7A11 or USP14 may significantly benefit BLCA patients with PSMD8 overexpression.