Shared genetic regulators and diagnostic biomarkers in gallbladder stone and cholangiocarcinoma: A comprehensive...

Gallbladder stone (GS) and cholangiocarcinoma (CHOL) are common biliary tract disorders that share certain clinical and pathological characteristics but exhibit distinct molecular hallmarks. While GS-related inflammation, cholestasis, and epithelial injury-repair responses may provide a biologically plausible link, the shared genetic mechanisms underlying the pathogenesis of both diseases remain largely unexplored. The aim of this study was to elucidate this shared genetic landscape using a comparative transcriptomic approach. We identified 671 and 5197 differentially expressed genes (DEGs) in the GS and CHOL datasets, respectively. Gene ontology and KEGG enrichment analysis of these DEGs revealed possible involvement in IL-17 signaling and bile acid metabolism. The overlap of the DEGs yielded 15 common genes, which were further refined to three core genes-CENPH, NRSN2, and SPDYC-using LASSO regression analysis. The expression levels of these core genes were validated across multiple datasets, and ROC analysis demonstrated that they exhibited robust diagnostic performance for distinguishing both GS and CHOL. The copy number variations and promoter methylation status of these core genes were also evaluated. Candidate drug compounds targeting these genes were predicted using the PubChem database, and a gene-compound interaction network was constructed to facilitate future therapeutic investigations. We further confirmed that CENPH was significantly upregulated in CHOL cell lines (HuCC-T1 and RBE) compared to normal human intrahepatic biliary epithelial cells. Subsequently, loss-of-function assays showed that CENPH was essential for the proliferation, migration, and invasion of CHOL cells. In conclusion, our findings provide new insights into the shared genetic regulators of GS and CHOL and highlight the potential for developing effective diagnostic tools and tailored therapeutic strategies.