Multi-omics analysis identifies CLDN1 as a key regulator of gallbladder cancer progression and prognosis

Gallbladder cancer (GBC) is a highly aggressive biliary tract malignancy characterized by poor prognosis and a lack of reliable biomarkers for early diagnosis. Despite its clinical aggressiveness, the molecular drivers and cellular regulatory networks underlying GBC progression remain incompletely characterized. In this study, we identified CLDN1 as a key epithelial-associated gene in GBC and revealed an epithelial-centered immune regulatory network potentially involved in tumor progression. Integrated bulk transcriptome and single-cell RNA sequencing (scRNA-seq) analyses revealed that CLDN1 is markedly upregulated in GBC, with expression localized predominantly in epithelial cells. At the single-cell level, epithelial cells emerged as a central hub of cell–cell communication, exhibiting extensive interactions with neutrophils, natural killer (NK) cells, and monocytes, thereby associating with immunosuppressive or inflammatory landscape of the tumor microenvironment (TME). Functional enrichment and intercellular interaction analyses suggested that CLDN1 -high epithelial cells promote immune modulation via cytokine secretion and facilitate TME remodeling and metastasis through crosstalk with mesenchymal and endothelial cells. Notably, GBC epithelial cells exhibited significantly higher CLDN1 expression compared to those in chronic cholecystitis, reinforcing its disease-specific relevance. By integrating differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches, CLDN1 was consistently identified as a key molecular feature of GBC. Collectively, our findings suggest that CLDN1 is closely associated with GBC initiation and progression through modulation of epithelial stability and epithelial–immune crosstalk, highlighting its potential as a biomarker for tumor classification, prognosis, and therapeutic targeting.