SOX9 protein in goblet cells as a critical mediator and potential therapeutic target in Barrett's esophagus: An...

Barrett's esophagus (BE) is the only recognized precursor to esophageal adenocarcinoma, yet current diagnostic and therapeutic strategies remain limited by sampling bias and lack of reliable molecular markers.

We conducted a multi-omics analysis using four bulk RNA-seq datasets for differential expression and WGCNA. Hub genes were identified through PPI networks and LASSO regression, validated in external cohorts. scRNA-seq profiled gene expression in epithelial and stromal subtypes, with immune profiling via CIBERSORT. SOX9 expression in single-cell resolution was validated in two BE patient cohorts.

Five upregulated genes-SOX9, COL1A2, SPARC, EPCAM, and KRT18-were identified as robust diagnostic markers, with AUC values >0.90. scRNA-seq showed increased SOX9 expression in goblet cells in BE, which was validated by IHC. SOX9 expression in goblet cells correlated with progression to high-grade dysplasia (HGD), while expression in non-goblet cells had a lower correlation. BE tissues showed distinct immune profiles, with enriched plasma cells and CD4⁺ memory T cells. Molecular docking identified potential druggable interactions with these proteins.

Our integrative analysis provides a comprehensive molecular and cellular atlas of BE. These findings enhance current understanding of BE pathogenesis and offer clinically relevant candidates for early detection and targeted intervention.