RAPGEFL1 as a Novel Prognostic Biomarker Correlated with Immune Infiltration and Drug Sensitivity in Kidney Renal Clear Cell Carcinoma

The aim of the study was to examine the clinical expression, prognostic value, and clinical treatment of Rap Guanine Nucleotide Exchange Factor Like 1 (RAPGEFL1) in kidney renal clear cell carcinoma (KIRC). Three GEO datasets, together with RNA-seq and clinical data from TCGA (541 KIRC and 72 normal tissues), were analyzed. Bioinformatics techniques included differential expression, survival (Kaplan-Meier, Cox regression), pathway enrichment (GSEA), immune infiltration (ssGSEA), stemness index (mRNAsi), and drug sensitivity analysis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate RAPGEFL1 expression in KIRC cell lines (OSRC-2 and A-498) compared with normal HK-2 cells. RAPGEFL1 was significantly upregulated in KIRC (p < 0.001) and showed high diagnostic value (AUC = 0.904). High expression independently predicted worse overall (HR = 2.05, p < 0.001), progression-free (HR = 1.50, p = 0.011), and disease-specific survival (HR = 2.30, p < 0.001). Multivariate Cox regression further identified RAPGEFL1 as an independent prognostic factor for overall survival (HR = 2.21, p < 0.001). It was associated with metabolite pathways, including oxidative phosphorylation and PPAR signaling, and decreased immune infiltration (T cells, macrophages), high immune checkpoints (CTLA4, LAG3), diminished stemness, and altered drug sensitivity (e.g., increased response to docetaxel). qRT-PCR revealed that it is overexpressed in KIRC cells. RAPGEFL1 overexpression identifies an aggressive KIRC subclass and may inform future personalized treatment strategies, including targeted therapy and immunotherapy, pending further validation. This study is the first to comprehensively characterize RAPGEFL1 as a prognostic biomarker in KIRC through integrative bioinformatics and experimental validation, revealing its dual role in immune modulation and drug response prediction.