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Life sciences · Journal article
Frontiers in Oncology · October 14, 2026
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Objectives Approximately 35% of patients with metastatic hormone-sensitive prostate cancer (mHSPC) progress to metastatic castration-resistant prostate cancer (mCRPC), highlighting the limitations of PSA as a stand-alone monitoring biomarker. This study aimed to construct a peripheral blood mRNA-based prognostic model for progression to mCRPC, evaluate the prognostic value of the identified biomarkers, and explore the biological role of the top-performing gene in prostate cancer cells. Methods Single-cell transcriptomic data (GSE288878) were analyzed to screen for mCRPC-related differentially expressed genes (DEGs). A prospective cohort study was conducted on newly diagnosed mHSPC patients who received first-line androgen deprivation therapy (ADT)-based treatment, from whom peripheral blood samples were collected for transcriptome sequencing. The intersection of DEGs from GSE288878 and our cohort defined the gene signature. Following random splitting of the dataset into development and validation sets (7:3), we used an Elastic Net-regularized Cox model to derive a prognostic model for mCRPC-free survival. TCGA prostate cancer samples were used to analyze the association between biomarker genes and progression-free survival (PFS). In vitro experiments investigated the biological role of the gene with prognostic significance in blood and cancer tissues. Results Five candidate genes (SLC25A39, GRB10, SELENBP1, SLC6A8, and YBX3) were identified as closely associated with mCRPC. We constructed a prognostic model, with an AUC for predicting 1-year mCRPC-free survival of 0.89 (0.80–0.97) in the development set and 0.83 (0.62–1.00) in the validation set. We identified elevated SLC6A8 expression in peripheral blood as an independent risk factor for progression to mCRPC. In the TCGA database, elevated SLC6A8 expression in prostate cancer tissue was identified as an independent risk factor for shorter PFS. Pharmacological inhibition of SLC6A8 significantly suppressed CRPC cell proliferation, decreased glycolytic metabolite levels, and downregulated glycolysis-associated gene expression. Conclusions The prognostic model effectively predicted progression to mCRPC in patients with mHSPC receiving first-line therapy. SLC6A8 may serve as a prognostic biomarker and promote prostate cancer progression through enhanced glycolysis.