MTRF1 reverses cisplatin resistance in bladder cancer by competitively disrupting OTUB1-mediated deubiquitination of SLC25A5 to trigger ferroptosis

Abstract Cisplatin (DDP)-based chemotherapy remains a standard treatment for advanced bladder cancer, yet acquired resistance remains a major cause of therapeutic failure. Here, we identify mitochondrial translation release factor 1 (MTRF1) as a critical suppressor of cisplatin resistance and a regulator of ferroptotic vulnerability in bladder cancer. MTRF1 was markedly downregulated in bladder cancer tissues and was further reduced in cisplatin-resistant clinical specimens as well as in T24-DDP and 5637-DDP resistant cell models. Restoration of MTRF1 significantly resensitized resistant cells to cisplatin, decreased IC50 values, and suppressed proliferation, colony formation, migration, and survival. Mechanistically, MTRF1 promoted a ferroptosis-prone state, as evidenced by elevated intracellular iron and malondialdehyde, increased Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), reduced Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and enhanced sensitivity to Erastin. MTRF1 also triggered mitochondrial membrane depolarization, reactive oxygen species accumulation, oxidative redox shift, a reduced GSH/GSSG ratio, and inhibition of the Nrf2/HO-1 antioxidant program, indicating a profound collapse of mitochondrial and redox homeostasis. At the molecular level, MTRF1 physically interacted with Solute Carrier Family 25 Member 5 (SLC25A5) and antagonized its pro-survival function. Further analyses demonstrated that MTRF1 promoted ubiquitin-proteasome-mediated degradation of SLC25A5 by increasing its polyubiquitination and competitively displacing the deubiquitinase OTUB1. In vivo, MTRF1 restoration enhanced cisplatin responsiveness in xenograft models, whereas deferoxamine partially reversed the antitumor effect, supporting a partial contribution of ferroptosis to this response. Collectively, these findings establish MTRF1 as a key determinant of cisplatin sensitivity in bladder cancer and uncover an MTRF1-OTUB1-SLC25A5 axis that links mitochondrial proteostasis to oxidative stress and ferroptotic cell death. Targeting this pathway may represent a promising strategy for overcoming cisplatin resistance in bladder cancer.