{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T07:00:49Z","timestamp":1785308449349,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82460367"],"award-info":[{"award-number":["82460367"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single\u2212cell RNA sequencing (GSE138709) with bulk transcriptomic datasets (TCGA\u2212CHOL, GSE107943, GSE32225) to systematically characterize the ICC cellular landscape. Analyses included CNV inference, stemness scoring, disulfidptosis activity assessment, and cell\u2212cell communication profiling. A diagnostic model was constructed using LASSO\u2212logistic regression with 10\u2212fold cross\u2212validation and validated in independent cohorts. TME characterization, survival analysis, and drug\u2212target screening were also performed. Experimental validation included HPA immunohistochemistry, qRT\u2212PCR, and functional assays following TMED3 knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seven major cell types were identified, with malignant cholangiocytes exhibiting high aneuploidy (74%), elevated stemness, upregulated disulfidptosis activity, and extensive communication via SPP1\u2212CD44 and IGFBP3\u2212TMEM219 networks. A five\u2212gene signature (TMED3, TMEM184B, MAPK13, MFSD10, GRB7) demonstrated robust diagnostic performance. Survival analysis showed borderline prognostic value for TMED3 (adjusted HR\u00a0=\u00a02.37, P\u00a0=\u00a00.073), while TMEM184B emerged as an independent prognostic factor (adjusted HR\u00a0=\u00a04.79, P\u00a0=\u00a00.028). PPI and co\u2212expression 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\u2212induced disulfidptosis. Network\u2212based drug screening identified eight high\u2212priority candidates for therapeutic repurposing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides a comprehensive single\u2212cell atlas of ICC, identifies TMED3 as a key regulator of a disulfidptosis\u2212related diagnostic signature, and demonstrates its functional role in promoting ICC malignancy. The five\u2212gene 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1858117","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:03:42Z","timestamp":1785305022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A TMED3-governed disulfidptosis-related diagnostic signature reveals tumor microenvironment remodeling in intrahepatic cholangiocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Wanjia","family":"Qiao","sequence":"first","affiliation":[{"name":"The First Clinical Medical College of Lanzhou University","place":["Lanzhou, 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