Ferro-aging-related DPEP1 as a prognostic and immunological target in clear cell renal cell carcinoma

Ferro-aging, an emerging concept linking ferroptosis and cellular senescence, remains poorly characterized in clear cell renal cell carcinoma (ccRCC). The clinical and immunological implications of ferro-aging-related genes (FARGs) in ccRCC have not been systematically explored. Transcriptomic and clinical data from TCGA-KIRC and E-MTAB-1980 cohorts were integrated with single-cell RNA sequencing data (GSE304466), spatial transcriptomics data (GSE175540), and 6 additional GEO datasets. Differential expression analysis identified ferro-aging-related differentially expressed genes (DEGs), which were subjected to functional enrichment, prognostic model construction via LASSO and multivariate Cox regression, immune landscape characterization, and drug sensitivity prediction. Single-cell analysis and virtual knockout of DPEP1 were performed using the “scTenifoldKnk” R package. In vitro functional assays, including CCK-8, colony formation, wound healing, and Transwell assays, were conducted in A-498 and OS-RC-2 ccRCC cells with DPEP1 overexpression. Intersection of 2,288 DEGs with 95 FARGs yielded 21 ferro-aging-related DEGs, which were enriched in pathways related to oxidative stress, immune inflammation, and HIF-1 signaling. A 9-gene FARGs score demonstrated prognostic performance in both training (5-year AUC = 0.702) and validation (5-year AUC = 0.778) cohorts. High FARGs score was associated with distinct immune infiltration patterns, elevated IC 50 values for sunitinib and pazopanib, and increased sensitivity to axitinib and sorafenib. DPEP1 showed the most favorable prognostic association, exhibiting tumor-specific downregulation across multiple cohorts. Single-cell analysis localized DPEP1 predominantly to endothelial cells and B cells, and virtual knockout perturbed antigen processing and presentation pathways. DPEP1 overexpression suppressed ccRCC cell proliferation, colony formation, migration, and invasion in vitro. DPEP1 is a ferro-aging-related tumor suppressor with favorable prognostic significance in ccRCC. The FARGs score provides a tool for risk stratification and therapeutic guidance. DPEP1 represents a promising prognostic and immunological target warranting further investigation.