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

BACKGROUNDBarrett'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.

METHODSWe 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.

RESULTSFive 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.

CONCLUSIONOur 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.