The Role of CD44, CALCOCO2, ALDH4A1, and CLEC16A in the Cross‐Talk Model of Epilepsy and Thyroid Cancer Progression

ABSTRACT Epilepsy and thyroid cancer are prevalent disorders with distinct etiologies; however, emerging evidence suggests the presence of shared molecular mechanisms that remain largely unexplored. In this study, we aimed to identify and characterize common hub genes and potential diagnostic markers linking these two conditions using comprehensive in silico and in vitro approaches. Differentially expressed genes (DEGs) were analyzed from epilepsy datasets (GSE44456, GSE186334) and thyroid cancer datasets (GSE60542, GSE153659), leading to the identification of four shared hub genes: CD44, CALCOCO2, ALDH4A1, and CLEC16A. Expression validation using RT‐qPCR confirmed consistent patterns, with CD44 and CLEC16A significantly upregulated and CALCOCO2 and ALDH4A1 downregulated in disease cell lines compared to controls. Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic potential for these genes in both diseases, with area under the curve (AUC) values exceeding 0.90. Functional enrichment and pathway analyses revealed that these genes are involved in oncogenic signaling, immune regulation, and tumor progression. Genetic alteration analysis indicated frequent mutations and copy number variations, while promoter methylation profiling suggested epigenetic regulation associated with disease outcomes. Survival analysis further identified ALDH4A1 and CLEC16A as prognostic markers. Moreover, in vitro and in vivo experiments demonstrated that CD44 and CLEC16A regulate cellular proliferation, migration, and clonogenicity through extracellular matrix (ECM)–receptor interactions involving CCL5, STAT3, CXCR4, and RAC1 signaling pathways. Collectively, these findings provide new insights into the shared molecular landscape of epilepsy and thyroid cancer, highlighting potential diagnostic biomarkers and therapeutic targets.