MXRA8, a key palmitoylation-related gene, promotes bladder cancer progression via remodeling tumor microenvironment and predicts poor prognosis

OBJECTIVE: The objective of this study was to comprehensively characterize the expression profiles and prognostic significance of palmitoylation-related genes (PRGs) in bladder cancer (BLCA). METHODS: Transcriptomic, clinical, and somatic mutation data of BLCA patients were obtained from The Cancer Genome Atlas (TCGA) and the GEO dataset (GSE13507), and batch effects were corrected using the ComBat method. Consensus clustering was performed to identify PRG-related molecular subtypes. Prognostic differentially expressed genes (DEGs) were further used for gene subtyping, and a PRG-based prognostic risk model was constructed by applying the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. CIBERSORT assessed immune infiltration, while scRNA-seq data from Tumor Immune Single-cell Hub (TISCH) analyzed core gene expression in cell clusters. The biological function of the core gene was validated by Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), Western blotting, wound-healing, colony-formation, and EdU assays. RESULTS: Two distinct PRG-related molecular subtypes and two gene subtypes were identified. The nine core genes (including MXRA8) showed robust predictive performance (AUC > 0.7 for 1-, 3-, and 5-year overall survival) and was incorporated into a nomogram along with clinical parameters. MXRA8 was highly expressed in BLCA tissues at both transcript and protein levels and predominantly expressed in fibroblast and myofibroblast clusters. Functionally, silencing MXRA8 significantly suppressed BLCA cell proliferation, migration, and invasion. CONCLUSIONS: The PRG-based risk score serves as a robust and clinically applicable tool for prognostic evaluation and predicting chemotherapy response. Furthermore, MXRA8 may serve as a potential molecular hub for developing precision medicine–oriented therapeutic strategies in BLCA.