A multi-omics analysis and clinical relevance of regulated cell death in bladder cancer

Haiwen Zhou^#, Yan Zhao,^#, Jingxian Li^#, Yuanjiong Qi, Yang Liu, Changwen Zhang, Yue Chen^*, Shiyong Qi^*, Zhihong Zhang^*
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
* Corresponding Author: Yue Chen. Email: email ; Shiyong Qi. Email: email ; Zhihong Zhang. Email: email
# Haiwen Zhou, Yan Zhao, and Jingxian Li Contributed equally to this article
(This article belongs to the Special Issue: Advances in Diagnosis and Management of Bladder Cancer: From Molecular Insights to Therapeutic Innovations)

Canadian Journal of Urology https://doi.org/10.32604/cju.2026.081481

Received 03 March 2026; Accepted 12 June 2026; Published online 14 August 2026

Abstract

Background: Regulated cell death (RCD) is critical for tumor progression and treatment response, but its integrated role in bladder cancer remains unclear. This study aimed to systematically characterize the cross-talk, multi-omics alterations, and clinical relevance of major RCD pathways in bladder cancer. Methods: Publicly available bladder cancer cohorts were analyzed to characterize the expression patterns and integrated regulation of major regulated cell death (RCD) programs. A curated set of 862 RCD-related genes was compiled from public databases and published literature, encompassing apoptosis, ferroptosis, pyroptosis, necroptosis, and autophagy-dependent cell death. Patients were stratified according to RCD-related transcriptional profiles, and associations with prognosis, tumor immune features, and therapeutic sensitivity were systematically evaluated. Selected RCD-associated hub gene was further examined through functional experiments in bladder cancer cell lines. Results: Extensive cross-talk among RCD-related genes was observed across genomic, epigenetic, and transcriptional levels. RCD gene expression was influenced by somatic mutation, copy number alteration, DNA methylation, and RNA modification. Bladder cancer patients (TCGA-BLCA, n = 402 for survival analysis) were stratified into two distinct RCD clusters demonstrating significantly different survival outcomes (log-rank p < 0.05), immune pathway enrichment, predicted immunotherapy responsiveness, and chemotherapy sensitivity profiles. RCD cluster 1 was predominantly associated with basal/squamous molecular subtypes, whereas RCD cluster 2 corresponded to luminal subtypes. Prognostic gene modules underlying cluster heterogeneity were identified. Among the identified hub genes, TIMP1 was functionally validated, and the silencing of TIMP1 significantly inhibited the proliferation and migration of bladder cancer cells (p < 0.05), supporting its association with aggressive tumor phenotypes identified from the RCD-related network. Conclusions: RCD-based molecular stratification defines clinically distinct bladder cancer subtypes associated with prognosis and therapeutic response. These findings provide a framework for personalized treatment strategies and support the translational potential of targeting regulated cell death pathways in bladder cancer.