{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T11:06:39Z","timestamp":1779015999465,"version":"3.51.4"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":131,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Portal vein tumor thrombosis (PVTT) and portal hypertension are major contributors to gastrointestinal bleeding in hepatocellular carcinoma (HCC), yet the molecular programs linking vascular pathology, immune dysregulation, and bleeding risk remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bulk transcriptomic datasets related to PVTT (GSE77509 and GSE69164) and noncirrhotic portal hypertension (GSE77627) were analyzed using differential expression and weighted gene coexpression network analysis to identify robust disease\u2010associated genes. A six\u2010gene core signature was derived by intersecting differentially expressed genes with intramodular hub genes across datasets. Bleeding risk\u2013associated biological programs, including coagulation, complement activation, angiogenesis, hypoxia, and inflammatory signaling, were quantified using ssGSEA. Immune infiltration was estimated using CIBERSORTx. Single\u2010cell RNA\u2010sequencing data from PVTT (GSE149614) were analyzed to resolve cell type\u2013specific expression patterns and intercellular communication. Associations with survival, DNA methylation, immune infiltration, drug sensitivity, and molecular interactions were evaluated using public cancer genomics resources. Functional validation was performed using siRNA\u2010mediated knockdown and drug treatment assays in HepG2 and Huh7 cells, followed by proliferation, colony formation, and wound healing assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Bleeding risk\u2013related biological programs exhibited dataset\u2010specific activation patterns and correlated with expression of the six\u2010gene signature. Single\u2010cell analysis revealed heterogeneous, cell type\u2013specific expression across malignant, stromal, endothelial, and immune populations. OGFRL1 and WDR62 were significantly associated with overall survival and showed methylation\u2010linked transcriptional regulation. Genetic silencing or pharmacological targeting of these genes significantly suppressed HCC cell proliferation, clonogenicity, and migration in vitro. Drug signature analysis and molecular docking supported potential interactions of nocodazole with OGFRL1 and testosterone with WDR62, which phenocopied knockdown effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify immune\u2013coagulation dysregulation as a molecular link between PVTT, portal hypertension, and gastrointestinal bleeding risk in HCC and functionally validate OGFRL1 and WDR62 as biologically and therapeutically relevant targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/7210691","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T10:23:46Z","timestamp":1778581426000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Convergent Immune\u2013Coagulation Programs Underlie Gastrointestinal Bleeding Risk in Portal Vein Tumor Thrombosis\u2013Associated Hepatocellular Carcinoma and Portal Hypertension"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-9187","authenticated-orcid":false,"given":"Xu","family":"Rutao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Zhuxiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao","family":"Jichun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0597-3245","authenticated-orcid":false,"given":"Zheng","family":"Tinghui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhang","family":"Kewei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wang","family":"Qingqing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Xiyang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weng","family":"Chengxin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-0629","authenticated-orcid":false,"given":"Huang","family":"Bin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_21_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00825-3"},{"key":"e_1_2_21_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-022-10188-1"},{"key":"e_1_2_21_3_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i32.7289"},{"key":"e_1_2_21_4_2","volume-title":"From Origins to Outcomes: Investigating the Complexity of Portal Hypertension in Etiology, Diagnosis, Treatment and Complications","author":"Helmberger T. M.","year":"2024"},{"key":"e_1_2_21_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0097-3"},{"key":"e_1_2_21_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17808"},{"key":"e_1_2_21_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.02.034"},{"key":"e_1_2_21_8_2","doi-asserted-by":"publisher","DOI":"10.1201\/9781003354062-5"},{"key":"e_1_2_21_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-46132-w"},{"key":"e_1_2_21_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-021-00635-z"},{"key":"e_1_2_21_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1390907"},{"key":"e_1_2_21_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-019-0613-5"},{"key":"e_1_2_21_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12102730"},{"key":"e_1_2_21_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14421"},{"key":"e_1_2_21_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2015.06.002"},{"key":"e_1_2_21_16_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.9005.3"},{"key":"e_1_2_21_17_2","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S340452"},{"key":"e_1_2_21_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559"},{"key":"e_1_2_21_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-328"},{"key":"e_1_2_21_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-1-54"},{"key":"e_1_2_21_21_2","volume-title":"2004 IEEE international joint conference on neural networks (IEEE Cat)","author":"Menke J.","year":"2004"},{"key":"e_1_2_21_22_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2024.1426274"},{"key":"e_1_2_21_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_2_21_24_2","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20253746"},{"key":"e_1_2_21_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32283-3"},{"key":"e_1_2_21_26_2","unstructured":"GhojoghB. GhodsiA. KarrayF. andCrowleyM. Uniform Manifold Approximation and Projection (UMAP) and Its Variants: Tutorial and Survey 2021 https:\/\/arxiv.org\/abs\/2109.02508."},{"key":"e_1_2_21_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes16070817"},{"key":"e_1_2_21_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39608-w"},{"key":"e_1_2_21_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12"},{"key":"e_1_2_21_30_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102971"},{"key":"e_1_2_21_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac558"},{"key":"e_1_2_21_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0273"},{"key":"e_1_2_21_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-03153-x"},{"key":"e_1_2_21_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg034"},{"key":"e_1_2_21_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv313"},{"key":"e_1_2_21_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv951"},{"key":"e_1_2_21_37_2","unstructured":"AcklooS. LiF. SzewczykM. SeitovaA. LoppnauP. ZengH. XuJ. AhmadS. ArnautovaY. A. BaghaieA. J. andBeldarS. A. A Resource to Enable Chemical Biology and Drug Discovery of WDR Proteins 2004 https:\/\/www.biorxiv.org\/content\/10.1101\/2024.03.03.583197v1.abstract."},{"key":"e_1_2_21_38_2","first-page":"113","volume-title":"Computational Drug Discovery and Design","author":"Liu Y.","year":"2023"},{"key":"e_1_2_21_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16193247"},{"key":"e_1_2_21_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241612754"},{"key":"e_1_2_21_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.109301"},{"key":"e_1_2_21_42_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology13100765"},{"key":"e_1_2_21_43_2","volume-title":"Multi-Omics Modeling for the Recovery of Disrupted Biological Systems","author":"Park J.","year":"2023"},{"key":"e_1_2_21_44_2","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2025.2461631"},{"key":"e_1_2_21_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-018-2150-z"},{"key":"e_1_2_21_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-025-02723-3"},{"key":"e_1_2_21_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-024-00752-1"},{"key":"e_1_2_21_48_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03858-x"},{"key":"e_1_2_21_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu316"},{"key":"e_1_2_21_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-021-00292-x"},{"key":"e_1_2_21_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhip.2024.06.005"},{"key":"e_1_2_21_52_2","doi-asserted-by":"publisher","DOI":"10.22214\/ijraset.2023.54927"}],"container-title":["Human Mutation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/7210691","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/humu\/7210691","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/humu\/7210691","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T10:23:44Z","timestamp":1779013424000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/humu\/7210691"}},"subtitle":[],"editor":[{"given":"Run","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/humu\/7210691"],"URL":"https:\/\/doi.org\/10.1155\/humu\/7210691","archive":["Portico"],"relation":{},"ISSN":["1059-7794","1098-1004"],"issn-type":[{"value":"1059-7794","type":"print"},{"value":"1098-1004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"7210691"}}