Abstract / Summary
Abstract Background Uveal melanoma (UM) is a highly metastatic intraocular malignancy with limited therapeutic options. The role of cuproptosis, a novel copper-dependent form of cell death, and its key regulator PDHB, in UM, remains completely unexplored. This study aims to construct a cuproptosis-related prognostic model and explore the biological and clinical significance of PDHB in UM. Methods A prognostic signature based on cuproptosis-related mRNA (CRmRNA) was developed using data from the UM cohort in The Cancer Genome Atlas (TCGA) and explored in independent Gene Expression Omnibus (GEO) datasets. Multi-omics analyses, including functional enrichment, immune infiltration profiling and single-cell RNA sequencing, were employed to characterise the role of the core gene PDHB. Molecular docking simulations predicted interactions between PDHB and specific compounds. In vitro experiments, including PDHB knockdown and cell viability assays, were conducted for functional validation. Results A preliminary three-CRmRNA prognostic signature (PDHB, LIAS and DLAT) was constructed, which showed potential for stratifying UM patients into distinct risk groups in the TCGA cohort and two GEO datasets. PDHB was identified as the most significant contributor to the model. Bioinformatic analyses revealed that low PDHB expression was associated with an adverse prognosis, metabolic reprogramming and an immunosuppressive TME. Single-cell sequencing revealed that PDHB displayed a broad distribution across multiple cell types, including tumor cells and fibroblasts, suggesting potential roles in both tumor cell intrinsic and stromal functions. Experimental knockdown of PDHB significantly enhanced UM cell viability, confirming its tumor-suppressive function. Furthermore, low-risk patients exhibited higher predicted sensitivity to docetaxel, vinorelbine and GSK650394, and molecular docking suggested stable binding of these compounds to PDHB. Conclusion This study proposes a preliminary cuproptosis-related prognostic model for UM and suggests PDHB as a potential prognostic indicator. Low PDHB expression may facilitate tumor cell evasion from cuproptosis, thereby promoting tumor progression and reshaping the immune microenvironment. These findings offer fresh perspectives for the development of metabolic and immunotherapeutic approaches to combat UM.