{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:55:48Z","timestamp":1781708148775,"version":"3.54.5"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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>Hepatocellular carcinoma (HCC) remains difficult to treat, and molecular determinants that link malignant behavior to the innate immune microenvironment are still needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated two-sample Mendelian randomization using cis-eQTL and cis-pQTL instruments with tumor transcriptomics, immune deconvolution, DNA methylation analyses, single-cell RNA sequencing, and loss-of-function assays to prioritize and characterize MAPRE2 in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Multi-omics Mendelian randomization identified MAPRE2 as a concordant risk-increasing candidate across transcript and protein layers. MAPRE2 was overexpressed in tumors and associated with worse overall survival. MAPRE2-high tumors were enriched for complement activation, TNFA signaling via NF-kB, interferon gamma response, extracellular matrix remodeling, and epithelial-mesenchymal transition, and showed stronger macrophage-, neutrophil-, and dendritic-cell-related signatures together with lower immunophenoscores, consistent with an inflamed but immunosuppressed innate immune microenvironment. Single-cell analysis showed multicompartment expression of MAPRE2, and virtual knockout implicated metabolic, adhesion, and extracellular programs. DNA methylation was associated with MAPRE2 expression and outcome, whereas recurrent high-level somatic amplification was rare. In HepG2 and MHCC97 cells, MAPRE2 knockdown suppressed proliferation, invasion, and wound closure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      MAPRE2 marks an aggressive HCC-associated molecular state coupled to macrophage-enriched innate immune dysregulation and may represent a candidate biomarker and therapeutic target that warrants rescue,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , transplant-cohort, and external prognostic validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1849407","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:26:28Z","timestamp":1778732788000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MAPRE2 is associated with macrophage-enriched innate immune dysregulation and malignant phenotypes in hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiuqin","family":"An","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Shanxi Provincial People\u2019s Hospital","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyumeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, College of Public Health, Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinda","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runxi","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiusheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Shanxi Provincial People\u2019s Hospital","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.046","article-title":"Comprehensive and integrative genomic characterization of hepatocellular carcinoma","volume":"169","year":"2017","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression","volume":"53","author":"V\u00f5sa","year":"2021","journal-title":"Nat Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4084","article-title":"Control of microtubule organization and dynamics: two ends in the limelight","volume":"16","author":"Akhmanova","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1042\/CS20201500","article-title":"EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK\/ERK pathway by modulating microtubule dynamics","volume":"135","author":"Zhong","year":"2021","journal-title":"Clin Sci (Lond)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4594","DOI":"10.1038\/s41467-022-32283-3","article-title":"A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma","volume":"13","author":"Lu","year":"2022","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PloS Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac558","article-title":"GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels","volume":"24","author":"Liu","year":"2023","journal-title":"Brief Bioinform"},{"key":"B16","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: an update to the integrated cancer data analysis platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: an efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns (N Y)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3892\/wasj.2024.268","article-title":"Identification of common biomarkers affecting patient survival in cancers","volume":"6","author":"Singh","year":"2024","journal-title":"World Acad Sci J"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/lt.25731","article-title":"Role of molecular biomarkers in liver transplantation for hepatocellular carcinoma","volume":"26","author":"von Felden","year":"2020","journal-title":"Liver Transpl"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2016.03.001","article-title":"Serologic and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation: A systematic review and meta-analysis","volume":"30","author":"Pommergaard","year":"2016","journal-title":"Transplant Rev (Orlando)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1097\/LVT.0000000000000779","article-title":"Baseline oral microbiome associated with post-living donor liver transplant early complications within 6 months","volume":"32","author":"Babu","year":"2026","journal-title":"Liver Transpl"}],"updated-by":[{"DOI":"10.3389\/fimmu.2026.1904303","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1849407\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:09:03Z","timestamp":1781705343000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1849407\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":28,"alternative-id":["10.3389\/fimmu.2026.1849407"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1849407","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"article-number":"1849407"}}