Abstract
BACKGROUND: The prognosis and progression mechanisms of bladder cancer (BLCA) are highly heterogeneous, driven by complex genetic and epigenetic alterations. This study aimed to construct a robust prognostic signature using epigenetic modification-related genes and to investigate the underlying molecular mechanisms driving its predictive power. METHODS: We developed a prognostic signature by applying a machine learning-based approach to screen epigenetic genes in the TCGA (The Cancer Genome Atlas)-BLCA cohort. Its performance was rigorously evaluated against 101 other machine learning algorithms and 110 previously published signatures across four independent validation datasets (IMvigor210, E-MTAB-4321, GSE31684, GSE48075). Associations with clinical, genetic, and transcriptomic features were analyzed. Immune infiltration, cell-cell interactions, and drug responses were assessed using both bulk and single-cell RNA-seq data. The functional role of a key signature gene, YTHDC1 (YTH Domain-Containing 1), was investigated through in vitro assays. RESULTS: A six-gene epigenetic signature was constructed. It significantly stratified patients into high- and low-risk groups with distinct overall survival (median survival 20.5 vs. 86.8 months, HR = 2.12, p = 7.7e-7). Our signature demonstrated superior predictive accuracy (C-index and 1-year AUROC) compared to other models. High-risk scores correlated with adverse clinical features (e.g., advanced stage), elevated PD-1/PD-L1, higher genomic instability, and immunosuppressive microenvironments. Single-cell analysis revealed altered T-cell interactions in high-risk cases. Mechanistically, YTHDC1 was shown to bind and stabilize POU5F1 (OCT4) mRNA, thereby inhibiting proliferation and migration in BLCA cell lines (T24, 5637). This anti-tumor effect was dependent on POU5F1. CONCLUSION: The machine learning-derived epigenetic signature is a robust indicator of BLCA heterogeneity across multiple dimensions. YTHDC1, a core component, inhibits cancer progression by stabilizing POU5F1 mRNA, highlighting a novel regulatory axis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08010-7.