Comprehensive Characterization of Crotonylation-Related Long Non-Coding RNAs Reveals a Prognostic Signature and Functional Landscape in Bladder Cancer

Lysine crotonylation (Kcr), a novel post-translational modification, has emerged as a key epigenetic regulator implicated in diverse cellular processes and tumorigenesis. However, the biological and clinical relevance of crotonylation-related long non-coding RNAs (lncRNAs) in bladder cancer remains unexplored. Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) were used to identify crotonylation-related lncRNAs via correlation with known regulators. An 11-lncRNA prognostic signature was constructed using univariate Cox, LASSO, and multivariate Cox regression analyses. The prognostic model was validated via Kaplan-Meier analysis, ROC curves, and a nomogram. We performed functional enrichment analysis, assessed immune cell infiltration patterns, analyzed tumor mutation burden (TMB), predicted drug responsiveness, and identified consensus molecular subtypes. In vitro experiments assessed the biological functions of selected lncRNAs. The crotonylation-related lncRNA signature stratified patients into high- and low-risk groups with significantly different survival outcomes (P < 0.001). The model demonstrated robust predictive performance with AUCs of 0.748, 0.705, and 0.730 for 1-, 3-, and 5-year survival, respectively. High-risk patients exhibited enrichment of tumor-promoting pathways, higher immune and stromal scores, and distinct mutational and immunological profiles. Drug sensitivity analyses revealed potential therapeutic vulnerabilities in high-risk tumors. Consensus clustering identified three molecular subtypes with differential prognosis and immune characteristics. Functionally, NR2F2-AS1 and SOX2-OT promoted, while GUSBP11 suppressed, bladder cancer cell migration, invasion, and proliferation in vitro. This study presents a novel crotonylation-related lncRNA-based signature with strong prognostic and functional relevance in bladder cancer. The findings provide new insights into the epigenetic regulation of tumor progression and offer potential avenues for personalized therapy.