ArticleFrontiers in immunology2026
A TMED3-governed disulfidptosis-related diagnostic signature reveals tumor microenvironment remodeling in intrahepatic cholangiocarcinoma.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and limited treatment options. Disulfidptosis, a novel cell death pathway driven by disulfide bond accumulation, has emerged as a potential mechanism in cancer biology; however, its role in ICC remains unclear. Methods: We integrated single-cell RNA sequencing (GSE138709) with bulk transcriptomic datasets (TCGA-CHOL, GSE107943, GSE32225) to systematically characterize the ICC cellular landscape. Analyses included CNV inference, stemness scoring, disulfidptosis activity assessment, and cell-cell communication profiling. A diagnostic model was constructed using LASSO-logistic regression with 10-fold cross-validation and validated in independent cohorts. TME characterization, survival analysis, and drug-target screening were also performed. Experimental validation included HPA immunohistochemistry, qRT-PCR, and functional assays following TMED3 knockdown. Results: Seven major cell types were identified, with malignant cholangiocytes exhibiting high aneuploidy (74%), elevated stemness, upregulated disulfidptosis activity, and extensive communication via SPP1-CD44 and IGFBP3-TMEM219 networks. A five-gene signature (TMED3, TMEM184B, MAPK13, MFSD10, GRB7) demonstrated robust diagnostic performance. Survival analysis showed borderline prognostic value for TMED3 (adjusted HR = 2.37, P = 0.073), while TMEM184B emerged as an independent prognostic factor (adjusted HR = 4.79, P = 0.028). PPI and co-expression analyses established links between signature genes and disulfidptosis regulators. Functional experiments confirmed that TMED3 knockdown suppressed ICC cell proliferation, migration, and enhanced sensitivity to glucose deprivation-induced disulfidptosis. Network-based drug screening identified eight high-priority candidates for therapeutic repurposing. Conclusion: This study provides a comprehensive single-cell atlas of ICC, identifies TMED3 as a key regulator of a disulfidptosis-related diagnostic signature, and demonstrates its functional role in promoting ICC malignancy. The five-gene signature shows diagnostic and prognostic promise, and the drug screening offers preliminary leads for therapeutic repurposing, providing a foundation for precision diagnosis and targeted therapy in ICC.
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