NT5DC2 inhibits ferroptosis by stabilizing ACSL3 in bladder cancer

Abstract Ferroptosis, a form of regulated cell death, plays a pivotal role in the development and treatment of cancer because of its impact on tumor cell proliferation, differentiation, and resistance to chemotherapy. NT5DC2, a gene associated with ferroptosis, has been identified as a key facilitator of cellular proliferation and metastasis in several cancers. In this study, we found that NT5DC2 is highly expressed in bladder cancer tissues compared with normal tissues and that its expression is correlated with the poor prognosis of bladder cancer patients. Functionally, we demonstrated that NT5DC2 suppresses ferroptosis in bladder cancer cells and promotes malignant tumor progression. Mechanistically, NT5DC2 interacts with ACSL3 and hampers its ubiquitination, thereby improving the stability of ACSL3, a crucial ferroptosis suppressing protein induced by oleic acid in lymph nodes. In addition, rescue assay results indicated that ACSL3 mediated the roles of NT5DC2 in suppressing ferroptosis of bladder cancer cells. Furthermore, we found that the upregulation of ACSL3 by oleic acid treatment was mediated by NT5DC2 as manifested by the observation that silencing of NT5DC2 abrogates this regulatory effect of oleic acid treatment. Collectively, our findings suggest that NT5DC2/ACSL3 plays a critical role in bladder cancer progression and ferroptosis regulation, suggesting that NT5DC2/ACSL3 is a potential therapeutic target for bladder cancer treatment.