USP15-mediated deubiquitination of FIS1 impairs mitochondrial function and sensitizes bladder cancer cells to radiotherapy.

While radiation therapy plays a pivotal role in the treatment of advanced invasive bladder cancer, its efficacy is often limited when used as alone, underscoring the need to identify molecular targets that regulate radiosensitivity. In this study, we identify USP15 as a novel regulator of mitochondrial function and demonstrate that USP15 serves as a key target for enhancing radiosensitivity in bladder cancer cells. In orthotopic bladder cancer mouse models, USP15 overexpression combined with radiotherapy effectively suppressed tumor growth. Mechanistically, as a canonical deubiquitinase, mitochondria-localized USP15 directly interacts with FIS1 and stabilizes FIS1 protein by deubiquitinating it at the K25 site, leading to mitochondrial dysfunction and downregulation of oxidative phosphorylation (OXPHOS), which in turn increases radiosensitivity. Conversely, treatment with the mitochondrial inhibitor metformin reversed the radioresistance observed in bladder cancer tissues with low USP15 expression, effectively inhibiting the growth of patient-derived xenograft (PDX) tumors and significantly improving survival benefits. In summary, USP15 plays a critical role in regulating radiosensitivity, and targeting USP15-mediated mitochondrial OXPHOS may represent a promising therapeutic strategy to enhance the efficacy of radiotherapy in bladder cancer, providing a novel treatment approach for the treatment of bladder cancer patients.