The Role of MIEF2 in Cisplatin Sensitivity in KIRP Patients: Insights from Four-gene Mitochondrial Fusion RNA Markers.

Background: Mitochondrial fusion is vital for cellular function and has been increasingly linked to cancer development. Kidney renal papillary cell carcinoma (KIRP), the second most common renal cell carcinoma, presents diverse prognostic outcomes. Identifying novel biomarkers is critical for improving prognosis and treatment response in KIRP.

Objective: This study aims to explore the gene expression associated with mitochondrial fusion and establish a novel gene signature model to predict KIRP prognosis and cisplatin sensitivity.

Methods: We analyzed RNA sequencing data and clinical records of 285 KIRP patients from The Cancer Genome Atlas (TCGA). LASSO regression identified four key mitochondrial fusion-related genes (BNIP3, GDAP1, MIEF2, PRKN). Multivariate Cox regression evaluated their association with overall survival. Risk stratification was developed based on gene expression. We assessed immunotherapy responses using checkpoint inhibitor scores, tumor mutation burden, TIDE scores, and tumor microenvironment characteristics. Cisplatin sensitivity was evaluated via correlation analysis of gene expression levels and half-maximal inhibitory concentration (IC50). In vitro loss- and gain-of-function experiments in KIRP cell lines (Caki-2, ACHN) assessed MIEF2's role in cisplatin sensitivity.

Results: The gene signature successfully stratified patients into high- and low-risk groups, with significant survival differences. The area under the ROC curve (AUC) for the risk model was 0.782. MIEF2 was notably associated with cisplatin sensitivity, confirmed through functional experiments. Patients in the high-risk group exhibited lower MIEF2 expression and increased cisplatin sensitivity.