Integration of a glutamine metabolism-based prognostic signature and a synergistic nanotherapeutic strategy targeting metabolic vulnerabilities in prostate cancer.

BACKGROUND: Prostate cancer (PCa) clinical management is challenged by tumor heterogeneity, driving the need for robust prognostic biomarkers, with altered glutamine metabolism emerging as a promising target. This investigation aimed to construct a metabolism-based prognostic signature for PCa and translate it into a targeted nanotherapeutic strategy. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to identify dysregulated glutamine metabolism genes and construct a prognostic model via univariate Cox, LASSO, and multivariate Cox regression with validation in an independent cohort. The model’s characteristics were assessed through tumor microenvironment (TME), tumor mutation burden (TMB), and consensus clustering analyses. The pivotal gene of the model was selected to functionally validate in vitro through proliferation, clonogenicity, migration, and invasion assays. To exploit this vulnerability, a CB/CDDP@lipo nanoplatform was engineered to co-deliver cisplatin and glutaminase inhibitor CB-839, with evaluation in PCa models in vitro and in vivo. RESULTS: A novel five-gene prognostic signature (ASNS, ATP2B4, GLYATL1, SLC6A20, SLC7A9) was established and stratified PCa patients into high- and low-risk groups based on progression-free interval (PFI). High-risk patients exhibited an immunosuppressive TME, higher TMB and TP53 mutations, and activation of proliferation-related pathways. Functional validation identified ASNS as a key oncogenic driver, enhancing PCa tumor cell proliferation, migration, and invasion. Therapeutically, CB/CDDP@lipo nanoplatform demonstrated potent synergistic cytotoxicity by depleting glutathione (GSH) and amplifying oxidative stress. This dual-action mechanism triggered significant apoptosis and tumor suppression with a favorable safety profile. CONCLUSIONS: Our study establishes a glutamine metabolism-based prognostic signature, pinpointing ASNS as a key driver. The resulting CB/CDDP@lipo nanoplatform offers a promising chemo-metabolic strategy for enhanced PCa treatment.