Ribosome biogenesis-related gene activity reveals immune features, prognostic differences, and FKBP4 targeting in metastatic melanoma

Patients with metastatic melanoma continue to have poor clinical outcomes. Although ribosome biogenesis-related genes (rbRGs) have been implicated in the initiation and progression of multiple malignancies, their expression landscape, biological roles, and clinical relevance in metastatic melanoma remain incompletely defined. In this study, we integrated single-cell RNA sequencing (scRNA-seq) data with bulk transcriptomic profiles and found that rbRG activity exhibited marked heterogeneity in metastatic melanoma and was associated with malignant biological features and poor prognosis. Given the important role of immune microenvironmental remodeling in tumor progression, we further stratified patients based on rbRG activity and found that different rbRG activity groups exhibited distinct immune microenvironmental states. This stratification also helped identify patient subgroups more likely to benefit from immunotherapy, suggesting its potential value for clinical stratification. To further investigate the relationship between rbRG activity and metastatic melanoma prognosis, we developed and validated a prognostic rbRG-related signature (rbRGS) using 101 machine-learning algorithm combinations, with univariable Cox regression identifying FK506-binding protein 4 (FKBP4) as a key prognostic gene. Virtual knockout analysis and in vitro experiments showed that FKBP4 knockdown suppressed malignant phenotypes and energy metabolism in melanoma cells. Finally, molecular docking, molecular dynamics simulations, and in vitro functional assays suggested that epigallocatechin-3-gallate (EGCG) may interact with FKBP4 and inhibit its function. Overall, this study provides new insights into patient stratification, biomarker discovery, and the prediction of immunotherapy response in metastatic melanoma. It also provides preliminary evidence for the potential role of FKBP4 in melanoma-associated malignant phenotypes and energy metabolism, supporting further investigation of EGCG as a candidate FKBP4-targeting compound.