# Peroxisomal activity drives aggressive bladder cancer phenotypes and reveals erythorbic acid as a potential therapeutic modulator

## TL;DR

Peroxisome activity in bladder cancer cells is linked to aggressive cancer traits, and a compound called erythorbic acid may help treat these cancers by targeting key enzymes.

## Contribution

A six-gene peroxisome-related signature was developed to identify bladder cancer subtypes, and erythorbic acid was identified as a potential therapeutic modulator.

## Key findings

- Two BLCA subtypes were identified based on peroxisome-related gene expression, differing in survival and metabolic profiles.
- Erythorbic acid showed strong binding to key peroxisomal enzymes and reduced cancer cell viability in vitro.
- Normal urothelial cells were less affected by erythorbic acid, suggesting selective targeting of cancer cells.

## Abstract

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.