Abstract

Bladder cancer is a common and aggressive disease with limited treatment options, highlighting the urgent need for new therapeutic strategies. Although mitochondrial proteins have been implicated in cancer progression, their role in bladder cancer remains unclear. This study aimed to investigate the function of the mitochondrial protease YME1L1 and its regulation by the E3 ubiquitin ligase TRIM21. By analyzing patient tissue samples, single-cell RNA data and performing experiments manipulating YME1L1 and TRIM21 levels in bladder cancer cells, we found that YME1L1 promotes cancer cell proliferation, invasion and mitochondrial energy production. Mechanistically, TRIM21 interacts with YME1L1 through its SPRY domain, facilitating K63-linked polyubiquitination of YME1L1 and accelerating its degradation. Furthermore, the K237 residue of YME1L1 is critical for TRIM21-mediated ubiquitination. These findings suggest that targeting the TRIM21–YME1L1 pathway could offer a novel strategy to inhibit bladder cancer progression.