PSMD11 stabilizes PGM3 by antagonizing Parkin to promote bladder cancer progression through energy metabolism reprogramming.

Bladder cancer (BCa), a highly prevalent and aggressive tumor of the urinary system, typically exhibits poor clinical outcomes, particularly in advanced stages where therapeutic efficacy remains inadequate. A key characteristic of tumorigenesis, metabolic reprogramming, contributes substantially to cancer cell proliferation and metastatic progression. In the current investigation, phosphoglucomutase 3 (PGM3) was markedly overexpressed in BCa tissues, with elevated PGM3 expression strongly associated with unfavorable prognosis. Downregulation of PGM3 inhibited BCa tumor growth and metastasis by suppressing energy metabolism pathways, including glycolysis and oxidative phosphorylation (OXPHOS). Mechanistically, proteasome 26S subunit non-ATPase 11 (PSMD11) interacted with PGM3, reducing its ubiquitination and proteasomal degradation. Additionally, Parkin acted as a ubiquitinase, destabilizing PGM3, whereas PSMD11 competed with Parkin for PGM3 binding, thereby attenuating Parkin-mediated ubiquitination and stabilizing PGM3. Further analysis demonstrated that PSMD11 enhanced glycolysis and OXPHOS through PGM3, promoting BCa malignancy. Higher PSMD11 expression positively correlated with increased PGM3 expression. Collectively, these findings suggest that targeting the PSMD11/PGM3 axis could provide a promising therapeutic strategy for BCa.