Multi-omic analysis constructs ferroptosis subtypes and risk signature and reveals that PEBP1 is an important tumor suppressor in kidney cancer.

Ferroptosis, an iron-dependent type of regulated cell death driven by excessive lipid peroxidation, plays an important role in natural tumor suppression. In this study, we identified 23 ferroptosis-related genes associated with prognosis in kidney cancer datasets. Based on the expression profiles of these genes, we classified kidney cancer into four distinct subtypes and constructed a 9-gene risk score to predict the prognosis of patients. Our analysis revealed that patients classified into group III and those in the low-risk group demonstrated significantly better survival probability. Moreover, the risk score exhibited strong predictive accuracy for the prognosis of kidney renal clear-cell carcinoma (KIRC) patients. Among the identified genes, PEBP1 showed elevated expression in both subtype III and the low-risk group, suggesting that it may act as a critical tumor suppressor. To further evaluate this, we examined PEBP1 expression patterns and their clinical correlations using TCGA-KIRC and KIRP cohorts. The results indicated that PEBP1 deletion was strongly associated with poor prognosis, while reduced PEBP1 expression correlated with advanced disease progression in both KIRC and KIRP patients. Functional enrichment analysis suggested that PEBP1 may be involved in pathways related to fatty acid metabolism and oxidative phosphorylation. Experimental validation supported these findings, showing that PEBP1 overexpression suppressed the proliferation and migration of kidney cancer cells. Additionally, PEBP1 promoted the accumulation of lipid reactive oxygen species (ROS), an effect that was reversed by a ferroptosis inhibitor. Conversely, silencing PEBP1 counteracted the lipid ROS induced by RSL4, a ferroptosis activator. In summary, our results demonstrate that PEBP1 functions as a potential tumor suppressor in kidney cancer and may serve as a promising prognostic biomarker and therapeutic target.