The GAP43/RAC1 axis drives glycolytic reprogramming and progression in lung adenocarcinoma

Abstract Background Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and poses a significant threat to public health. Traditional treatments often lead to poor prognoses and tumor recurrence. Glycolysis plays a crucial role in the initiation and progression of LUAD, making it an important area of research for the development of new therapeutic strategies. Methods In this study, we analyzed the Cancer Genome Atlas (TCGA) data to assess GAP43 expression and prognostic value in LUAD. Functional roles were investigated using GAP43 knockdown and overexpression cell lines through proliferation, apoptosis, colony formation, wound healing, and Transwell assays. The nude mouse xenograft tumor model was used to validate the effects of GAP43 knockdown on tumor growth in vivo. RAC1 was identified as a downstream target via gene set enrichment analysis (GSEA) and correlation analysis. Glycolytic activity (glucose uptake, ATP/lactate production, OCR/ECAR) and related protein expression were measured, and GAP43-RAC1 interaction was examined by co-immunoprecipitation. Results GAP43 expression was significantly upregulated in LUAD tissues compared with normal tissues and that high GAP43 expression was associated with poor overall survival (OS) and progression-free survival (PFS). GAP43 knockdown significantly inhibited the proliferation, migration, and invasive capabilities of LUAD cells in vitro and suppressed tumor growth in vivo. Conversely, its overexpression promoted malignant behavior of tumor cells. Mechanistically, GAP43 promoted the transcription of RAC1 by binding to the transcription factor CREB1, thereby enhancing aerobic glycolysis and facilitating the malignant progression of LUAD. Conclusions The results of this study suggest that GAP43 may serve as a potential therapeutic target for LUAD. The GAP43/RAC1 axis plays a crucial role in regulating glycolysis and malignant phenotypes in LUAD cells, offering new insights for the clinical management of LUAD.