Peroxisomal activity drives aggressive bladder cancer phenotypes and reveals erythorbic acid as a potential...

Peroxisomes play essential roles in cellular lipid metabolism and redox regulation, yet their contribution to bladder cancer (BLCA) progression remains poorly defined.

Transcriptomic and clinical data from TCGA-BLCA and three GEO cohorts were integrated to identify prognostic peroxisome-related genes (PRGs). A six-gene PRG signature was constructed and validated for survival prediction, molecular subtype stratification, and pathway enrichment analyses, with expression validation in bladder cancer cell lines. Drug-gene enrichment and molecular docking were then performed to identify potential therapeutic modulators, which were subsequently assessed using CCK-8 cell viability assays.

Two distinct PRG-based molecular subtypes of BLCA were identified, showing significant differences in survival, mutational landscape, immune infiltration, and metabolic signaling. The high-risk subtype was enriched for PRDX1, ACOX2, and IDI1, reflecting enhanced oxidative stress adaptation and metabolic reprogramming, while the low-risk group was defined by ACSL5 and XDH. Drug-gene enrichment identified erythorbic acid, a redox-active ascorbate analog, as the most biologically relevant compound targeting high-risk PRGs. Molecular docking confirmed stable binding of erythorbic acid to ACOX2 (-6.2 kcal/mol), IDI1 (-6.6 kcal/mol), and PRDX1 (-5.4 kcal/mol) within catalytically active pockets, suggesting coordinated modulation of oxidative metabolism and redox balance. Subsequent CCK-8 assays demonstrated a dose- and time-dependent reduction in viability in bladder cancer cell lines. In contrast, normal urothelial XV-HUC-1 cells showed relatively preserved viability, indicating differential cellular responses to erythorbic acid in vitro.

Peroxisome-related gene dysregulation shapes the metabolic and immunologic heterogeneity of bladder cancer. Erythorbic acid emerges as a promising redox-metabolic modulator targeting multiple peroxisomal enzymes, offering a potential therapeutic avenue for aggressive, high-risk BLCA subtypes.