Evaluating Potential Therapeutic Targets and Drug Repurposing Based on the Esophageal Cancer Subtypes

<b>Background:</b> Esophageal cancer (EC), including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), remains a lethal malignancy with limited molecularly tailored treatment options. Due to substantial histologic and transcriptomic differences between subtypes, therapeutic responses often vary, underscoring the need for subtype-stratified analysis and precision drug discovery. <b>Methods:</b> We integrated transcriptomic data from GEO and TCGA to identify differentially expressed genes (DEGs) specific to EAC, ESCC, and their shared profiles. Functional enrichment (GO, KEGG) and protein-protein interaction (PPI) network analyses were conducted to extract hub genes using DAVID, STRING, and Cytoscape. Survival associations were evaluated using TCGA-ESCA and UALCAN. Drug repurposing was performed using L1000FWD, L1000CDS2, and SigCom LINCS. <b>Results:</b> We identified 79, 59, and 17 hub genes in the DEG-EAC, DEG-ESCC, and DEG-EAC&ESCC datasets, respectively. In EAC, 16 novel hub genes including SCARB1, SERPINH1, and DSC2 were discovered, which had not been previously implicated in this subtype. These genes were significantly enriched in pathways related to extracellular matrix (ECM) remodeling and epithelial structure. In addition, shared hub genes across EAC and ESCC-such as COL1A1, SPARC, and MMP1-were enriched in ECM organization and cell adhesion processes, highlighting convergent tumor-stroma interactions. Drug repositioning analysis consistently prioritized MEK inhibitors, trametinib and selumetinib, as potential therapeutic candidates across all DEG datasets. <b>Conclusions:</b> This study presents a comprehensive, subtype-stratified transcriptomic framework for EC, identifying both unique and shared hub genes with potential functional relevance to ECM dynamics. Our findings suggest that ECM remodelers may serve as therapeutic targets, and highlight MEK inhibition as a promising, yet exploratory, repurposing strategy. While these results offer a molecular foundation for future precision oncology efforts in EC, further validation through proteomic analysis, functional studies, and clinical evaluation is warranted.