Lactate Dehydrogenase A and a Novel Four‐Gene Signature as Dual Diagnostic Markers for Lung Adenocarcinoma and Ischemic Stroke

ABSTRACT Background Lung adenocarcinoma (LUAD) and ischemic stroke (IS) are major global health challenges that share underlying molecular mechanisms; however, the extent of this overlap remains unclear. This study explores gene expression changes and protein interactions that link these two conditions to identify diagnostic biomarkers and to examine the role of lactate dehydrogenase A (LDHA) in LUAD progression. Methods Transcriptomic data from The Cancer Genome Atlas LUAD dataset, the Gene Expression Omnibus GSE146882 IS dataset, and, for validation, the GSE31210 LUAD dataset were subjected to differential expression analysis using DESeq2 and limma packages. Differentially expressed genes that were common between the LUAD and IS datasets were analyzed through protein‐protein interaction network construction and machine learning algorithms (Support Vector Machine and Random Forest) to identify diagnostic biomarkers. Diagnostic accuracy was assessed using receiver operating characteristic curve analysis. For LUAD, prognostic significance was determined through Cox regression analysis, and immune infiltration patterns were characterized using the CIBERSORT algorithm. Associations with N6‐methyladenosine modification genes and cell cycle regulators were analyzed through correlation studies. Results Eighty‐five upregulated genes were common between LUAD and IS tissues, among which 49 hub genes were identified through protein‐protein interaction analysis. Machine learning selected a four‐gene signature, LDHA , NME4 , SLC25A39 , and SLC7A5 , which showed high diagnostic accuracy. In LUAD, LDHA was the only independent prognostic factor linked to poor survival. Furthermore, LDHA expression was positively correlated with key N6‐methyladenosine modification genes and cell cycle regulators and was linked to a distinct pro‐inflammatory immune infiltration pattern. Conclusions We have identified LDHA and three additional hub genes as disease‐agnostic diagnostic biomarkers in LUAD and IS. The independent prognostic significance of LDHA and its broad mechanistic involvement establish it as a potential therapeutic target for LUAD management. Further investigation of LUAD–IS comorbidity mechanisms is warranted.