A FOXO1-G6PC transcriptional axis restrains renal cell carcinoma progression: multi-omics, epigenetic, and mechanistic evidence.

G6PC has emerged as a prognostic biomarker and potential therapeutic target in cancer, but its role in renal cell carcinoma (RCC) remains unclear. We analyzed G6PC expression using TCGA, GEO, and clinical data, with protein validation via HPA. Pathway enrichment, immune infiltration, and methylation analyses were performed. Prognostic value was assessed by Cox regression and Kaplan-Meier analysis. In vitro and in vivo experiments evaluated the effects of G6PC dysregulation. Transcriptome sequencing, ChIP-qPCR, and dual-luciferase reporter assays were used to identify upstream transcriptional regulators. G6PC was significantly downregulated in RCC and inversely correlated with TNM stage, grade, and immune infiltration. Hypomethylation of G6PC was observed. Enrichment analyses linked G6PC to BCR signaling and ECM-related pathways. Overexpression of G6PC inhibited RCC cell proliferation and migration. Mechanistically, FOXO1 was validated as a direct transcriptional regulator of G6PC, as demonstrated by enrichment of FOXO1 binding on the G6PC promoter (ChIP-qPCR) and promoter activation in dual-luciferase assays. Furthermore, G6PC exerted negative feedback on FOXO1 signaling, establishing a bidirectional regulatory loop. G6PC functions as a tumor suppressor in RCC and is directly transcriptionally activated by FOXO1, forming a FOXO1-G6PC axis that restrains RCC progression. This mechanistic insight highlights G6PC as a promising therapeutic and prognostic target.