Cathepsin V ( CTSV ) Shapes the Epigenetic–Immune Landscape of Bladder Cancer and Emerges as a Noninvasive Biomarker

ABSTRACT Objective The aim of this study was to perform a comprehensive characterization of CTSV regulation in bladder cancer (BC) and its association with clinicopathological features, prognosis, and tumor stroma modulation using multi‐omics databases. Methods We used integrative bioinformatics approaches with publicly available multi‐omics datasets. CTSV expression was evaluated across BC cohorts using TIMER2.0, GEPIA, GENT2, and GEO databases, while protein expression was examined with the Human Protein Atlas. Genomic alterations, DNA methylation, and histone modifications were analyzed using TCGA, UALCAN, ASD MethSurv, SMART, and DepMap databases. Associations with clinical outcomes, immune infiltration, and drug sensitivity were investigated through TCGA, CIBERSORT, TISIDB, single‐cell and spatial transcriptomics, and RNAactDrug platforms. Results We found that CTSV was upregulated in BC, especially in non‐papillary tumors. Moreover, its expression correlated positively with tumor grade, the presence of distant and lymph node metastases, resistance to therapy, and poorer overall and progression‐free survival. Furthermore, CTSV expression was associated with mutations in known BC driver genes ( TP53 , RB1 , and ERBB2 ) and showed a correlation with promoter hypomethylation, gene body methylation, and histone markers (e.g., H3K18ac1K23ac0), suggesting an epigenetic mechanism driving CTSV expression. The CTSV high and CTSV low groups exhibited a different stromal composition, with the former showing a more immunogenic signature. Finally, we found that cell lines and tumors highly expressing CTSV exhibit higher sensitivity to multiple chemotherapeutic drugs. Conclusion CTSV overexpression is associated with bladder cancer aggressiveness through epigenetic regulation and immune modulation, emerging as a promising prognostic biomarker and noninvasive diagnostic target.