Exploring the Glycolytic Mechanisms in "Driver Gene-Negative" Lung Adenocarcinoma (LUAD): A Single-Cell RNA Sequencing Approach to Identify the MIF-HIF-1α Axis.

Background: Patients with "driver gene-negative" LUAD lack effective targeted therapies. This study aimed to elucidate the role of the glycolysis pathway in driver gene-negative LUAD to identify key genes and potential therapeutic targets. Methods: Bulk RNA sequencing data from 49 patients with driver gene-negative LUAD were analyzed. The driver gene-negative status of patients was confirmed by immunoblotting. Gene set enrichment analysis (GSEA) was conducted on six hallmark pathways related to glycolysis. Additionally, key genes were identified and a risk score model was constructed. Finally, single-cell RNA sequencing data were processed using the Seurat package for data cleaning, dimensionality reduction clustering, and cell type identification. Results: GSEA analysis revealed significant enrichment of the glycolysis pathway in driver gene-negative LUAD. Differential expression analysis identified 144 genes associated with the glycolysis pathway. Six glycolysis-related genes (ANKZF1, GPR87, KIF2A, LCT, MIF, SDHC) were identified associated with poor prognosis. Single-cell sequencing analysis validated the key role of MIF in the glycolysis process and revealed a positive feedback regulatory axis between MIF and HIF-1α, which may promoting glycolysis and malignant transformation. Conclusion: This study elucidated glucose metabolic reprogramming mechanisms and highlighted the MIF-HIF-1α axis as a promising therapeutic target in "driver gene-negative" LUAD, which may offer new avenues for improving outcomes, particularly those lacking conventional targeted therapy options.