New insights into lysosomal ferroptosis-related prognostic signatures in prostate cancer: evidence from bulk and single-cell transcriptomic analysis
Background Prostate adenocarcinoma (PRAD) is a leading reason of cancer-related death in men worldwide, yet reliable biomarkers for accurate risk stratification are lacking. This study sought to build and test a lysosomal ferroptosis-related prognostic risk model for PRAD. Methods This study merged single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets. Differentially expressed genes (DEGs) from the TCGA-PRAD cohort were intersected with 39 lysosomal ferroptosis-related genes (LFRGs). Univariate Cox regression and random survival forest (RSF) algorithms were applied to build a prognostic risk model, which was validated in two separate cohorts (GSE70768; GSE70769). Immune infiltration, drug sensitivity, and single-cell transcriptomic analyses were subsequently performed. Finally, the expression and potential mechanism of hub genes were investigated in experimental samples. Results Seven candidate genes were identified, from which MMD and FTH1 were chosen to create a prognostic risk model. The model achieved AUC values of 0.90, 0.89, and 0.87 at 1-, 2-, and 3-year timepoints in TCGA-PRAD, with consistent performance across both validation cohorts. High-risk patients displayed an immunosuppressive microenvironment noted for enhanced myeloid-derived suppressor cells, regulatory T cells, upregulation of 23 immune checkpoint genes, higher TIDE scores, and increased tumor mutational burden (TMB). Drug sensitivity analysis identified differential responses to 3 agents after FDR correction. Single-cell analysis revealed myeloid-predominant expression of MMD and FTH1, with divergent pseudotime kinetics and enhanced KRAS, IL2-STAT5, and mTORC1 signaling, with MIF–CD74 as a key intercellular communication axis. The hub genes were validated in experimental samples and these findings suggest a potential therapeutic strategy combining FTH1 degradation with PD-L1 blockade, although the immunological mechanisms require further validation in immunocompetent models. Conclusion This study presented a novel and potentially useful lysosomal ferroptosis-related prognostic risk model that effectively stratified PRAD patients by survival outcome and therapeutic response, providing a valuable framework for personalized clinical decision-making.