: Barrett's esophagus (BE), with metaplastic columnar epithelium in the lower esophagus, predisposes patients to esophageal adenocarcinoma (EAC). Despite extensive research, mechanisms underlying BE progression to EAC remain unclear, and no validated biomarkers are available for clinical use. Progastricsin/Pepsinogen-C (PGC), an aspartic proteinase linked to maintaining normal epithelial morphology, is often absent in advanced gastrointestinal malignancies. This study comprehensively investigates PGC expression across cancers, particularly in esophageal cancer (ESCA), to clarify its role in BE progression to EAC. : We utilized multiple bioinformatic platforms (TIMER, UALCAN, cBioPortal, GEPIA, STRING, Metascape, and GEO database) to assess expression, genomic alterations, and correlations with clinicopathological features, survival, and immune infiltration. Additionally, using the GEO dataset, we compared non-dysplastic Barrett's esophagus (NDBE) patients with those who progressed to malignancy, identifying differentially expressed genes (DEGs), their interactions, and potential roles in progression. : was notably upregulated in various cancers, especially in adjacent normal tissues of ESCA. Genomic amplifications of were linked to improved survival in EAC patients, particularly those with high expression, suggesting a protective role. Moreover, expression positively correlated with favorable immune infiltration, notably B cells and CD8+ T cells. Enrichment analysis of downregulated DEGs revealed significant involvement in key biological processes, specifically in extracellular matrix organization. Among the downregulated DEGs, we identified among the top 10 hub genes, underscoring its role in tissue homeostasis. : These findings suggest that could serve as a promising biomarker for predicting the high-risk transformation from BE to EAC, offering new insights into EAC progression and future therapeutic targets.