{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:56Z","timestamp":1785434876538,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"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":["No. 82474682"],"award-info":[{"award-number":["No. 82474682"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["No. 82474682"],"award-info":[{"award-number":["No. 82474682"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) is a chronic inflammatory precursor associated with an increased risk of intrahepatic cholangiocarcinoma (ICC), yet identifying malignant features within the persistent inflammatory background remains challenging. In this study, a background-deviation framework was applied to explore malignant-associated determinants during PSC-associated cholangiocarcinogenesis. Single-cell RNA sequencing data from PSC, ICC tumor tissues, and adjacent non-tumor tissues were integrated, followed by functional enrichment, CellChat analysis, Monocle 2 pseudotime reconstruction, Non-negative Matrix Factorization (NMF), STRING\/Cytoscape network analysis, and diagnostic signature construction using LASSO regression and exhaustive best subset selection. Single-cell profiling suggested disease-associated cellular remodeling, including cholangiocyte expansion in ICC samples. Functional and intercellular communication analyses indicated a putative transition from an immune-dominant PSC state toward a hyper-biosynthetic ICC-associated phenotype, accompanied by a possible MIF receptor-usage shift from CXCR4 to CD44. Monocle 2 and NMF further identified candidate malignant-associated trajectories and meta-programs, with MYC\/TP63-related regulatory signals emerging as potential contributors. Based on these exploratory findings, best subset selection identified a two-gene transcriptomic candidate signature comprising PMAIP1 and GADD45A, which showed promising discriminative performance in internal cross-validation and an external tumor-versus-adjacent validation cohort. These findings provide a transcriptomic basis for further validation of PSC-associated cholangiocarcinogenesis and potential ICC surveillance markers.<\/jats:p>","DOI":"10.3390\/ijms27114826","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"4826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Dual-Gene Signature of PMAIP1 and GADD45A for Early Detection of Intrahepatic Cholangiocarcinoma in the Context of Primary Sclerosing Cholangitis"],"prefix":"10.3390","volume":"27","author":[{"given":"Bei","family":"Yao","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Guan","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiguang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Jia","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinli","family":"Shi","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-6601","authenticated-orcid":false,"given":"Zhiyong","family":"Hou","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.canlet.2015.09.008","article-title":"Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management","volume":"379","author":"Zhang","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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