Pan-cancer analysis reveals the prognostic relevance of NUP54 and its association with HIF-1α-related glycolytic phenotypes in lung adenocarcinoma

The role of the nuclear pore protein NUP54 in tumorigenesis and progression remains unclear. By integrating multiomics data from TCGA, GTEx, CPTAC, and Other sources, in this study, the first pan-cancer landscape of NUP54 was systematically delineated: its mRNA and protein expression levels are significantly upregulated in most types of Cancer, including lung adenocarcinoma, hepatocellular carcinoma, and gastric Cancer. It has a high diagnostic value across several types of Cancer, including cholangiocarcinoma and pancreatic Cancer. Its prognostic value has high tissue specificity: serving as an independent risk factor in low-grade glioma, lung adenocarcinoma, and pancreatic Cancer, while protecting against renal clear cell carcinoma. Focusing on lung adenocarcinoma, multi-cohort clinical assessment, single-cell transcriptomics analysis, and functional experiments confirmed that high expression of NUP54 is an independent predictor of poor patient prognosis and significantly promotes the proliferation of Cancer cells, colony formation, and in vivo tumorigenesis. NUP54 activates the HIF-1α signaling pathway to upregulate key glycolytic molecules LDHA, PKM2, and GLUT1, thereby driving glucose uptake, lactate production, and high ATP levels to promote metabolic reprogramming. This NUP54-associated phenotype was attenuated by the HIF-1α Inhibitor PX-478 in vitro and in vivo. Overall, this study identifies NUP54 as a potential prognostic biomarker in LUAD and suggests that the NUP54/HIF-1α/glycolysis-related pathway may represent a biological mechanism worthy of further investigation.