Identification of a novel ferroptosis-inducing micropeptide in bladder cancer

Bladder cancer (BC) is a common malignancy in males, and currently lacks ideal therapeutic approaches. Exploring emerging therapeutic targets from the perspective of endogenous peptides to improve the prognosis of bladder cancer patients holds promise. In this study, we have identified CTSGDP-13, a novel endogenous peptide, which demonstrates potential anti-cancer effects in BC. Our findings reveal that CTSGDP-13 can promote ferroptosis in BC cells, both in vitro and in vivo, leading to the inhibition of BC progression. Furthermore, we have identified TRIM25 as a downstream regulatory target of CTSGDP-13. The expression of TRIM25 is significantly upregulated in BC, and its inhibition of ferroptosis promotes BC progression. Mechanistic studies have shown that CTSGDP-13 promotes the ubiquitination and subsequent degradation of TRIM25 by disrupting its interaction with the deubiquitinase USP7. Further investigations indicate that CTSGDP-13 promotes ferroptosis in BC by regulating the USP7/TRIM25/KEAP1 axis. The elucidation of the functional mechanisms of natural CTSGDP-13 and TRIM25 holds promise in providing valuable therapeutic targets for BC diagnosis and treatment. •CTSGDP-13 is a novel peptide that significantly down-regulated in BC.•CTSGDP-13 facilitates the ferroptosis of BC cells.•TRIM25 is up-regulated in BC and inhibits the ferroptosis of BC cells.•CTSGDP-13 can bind and regulate TRIM25 by disrupting the interaction between deubiquitinase USP7 and TRIM25.•CTSGDP-13 and TRIM25 could be the promising targets for BC.