Abstract
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.
Data availability
The transcription profiles of BCa patients were retrieved from the TCGA database. BLCA gene microarray expression profiles (GSE13507, GSE31684, GSE32548, GSE32894, and GSE48075) were obtained from the GEO database. The publicly accessible UROMOL cohort data were downloaded from ArrayExpress. Pan-cancer analyses of PGM3 and PSMD11 were performed using the TIMER database. Prognostic information for PGM3 and PSMD11 was acquired from PanCanSurvPlot. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This research was supported by the National Natural Science Foundation of China (No. 82260598) and Jiangxi Provincial academic and technical leaders training program (20225BCJ22009) to Tao Zeng.
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YC, TC, GH Z, and TZ conceived the project and designed the study. YC, TC, GH Z, ZS, and GZ performed the experiments. GZ and YC collected the clinical tumor samples. YC, TC, SX, and XP R performed the data analysis. YC, TC, and GH Z wrote the paper. TZ provided the funding support.
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This study was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Nanchang University and was conducted in compliance with the principles of the Declaration of Helsinki.
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Cheng, Y., Chen, T., Zheng, G. et al. PSMD11 stabilizes PGM3 by antagonizing Parkin to promote bladder cancer progression through energy metabolism reprogramming. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08691-4
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DOI: https://doi.org/10.1038/s41419-026-08691-4
