{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:44:57Z","timestamp":1785912297560,"version":"3.56.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071558"],"award-info":[{"award-number":["82071558"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82141109"],"award-info":[{"award-number":["82141109"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science & Technology Commission","doi-asserted-by":"publisher","award":["Z241100009024044"],"award-info":[{"award-number":["Z241100009024044"]}],"id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although histologically benign, invasive pituitary adenomas exhibit malignant-like biological behavior, characterized by local invasiveness and high proliferative activity. Clinical management remains challenging due to the absence of effective targeted therapies, difficulties with surgical resection, and high risks of postoperative residual disease and recurrence. Precise therapeutic targets are urgently needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate molecular mechanisms underlying pituitary adenoma invasion and identify potential therapeutic targets, we collected 216 whole transcriptome sequencing datasets representing all pituitary adenoma lineages, along with several single-cell transcriptome datasets. The Scissor algorithm was utilized to identify invasion-associated cell subpopulations. Single-cell weighted gene co-expression network analysis delineated the underlying gene regulatory network. Differential gene expression and pathway enrichment analyses explored NNAT\u2013MAPK contributions to pituitary adenoma invasion. Findings were validated through in vitro and in vivo experiments (quantitative polymerase chain reaction, CCK-8, colony formation, Transwell assays, western blotting, immunohistochemistry, and multiplex immunofluorescence).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Multi-transcriptomics analysis comprehensively characterized the transcriptomic landscape of invasive pituitary adenomas and revealed active RNA interactions within these tumors, particularly between mRNAs and long non-coding RNAs. Specific cell subpopulations associated with invasiveness were confirmed at the single-cell level. Analysis of phenotype-associated gene regulatory networks within these subpopulations identified the NNAT\u2013MAPK\u2013p38 axis, which promotes epithelial\u2013mesenchymal transition in pituitary adenoma cells and drives invasion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings enhance understanding of the mechanisms underlying pituitary adenoma invasiveness and identify NNAT as a candidate for targeted therapy development, offering potential precision treatment strategies for patients resistant to conventional therapies or experiencing recurrent disease after surgery.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag113","type":"journal-article","created":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T11:32:56Z","timestamp":1779017576000},"page":"1953-1969","source":"Crossref","is-referenced-by-count":0,"title":["Multi-transcriptomics analysis identifies NNAT as a key molecule driving the invasive phenotype across all lineages of pituitary adenomas"],"prefix":"10.1093","volume":"28","author":[{"given":"Meng","family":"Liu","sequence":"first","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University , Beijing,","place":["China"]},{"name":"Department of Neurosurgery, Peking University Third Hospital, Peking University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejing","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxiaofeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8050-5680","authenticated-orcid":false,"given":"Zhaoyi","family":"Yi","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Xue","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0495-8711","authenticated-orcid":false,"given":"Qiuyue","family":"Fang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]},{"name":"Department of Neurosurgery, Sichuan Provincial People\u2019s Hospital, University of Electronic Science and Technology of China , Chengdu,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Gong","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]},{"name":"Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-1261","authenticated-orcid":false,"given":"Chuzhong","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]},{"name":"Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6029-8521","authenticated-orcid":false,"given":"Weiyan","family":"Xie","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University , Beijing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"2026080501512697700_noag113-B1","doi-asserted-by":"publisher","first-page":"bvaa205","DOI":"10.1210\/jendso\/bvaa205","article-title":"Pituitary neoplasm nomenclature workshop: does adenoma stand the test of time?","volume":"5","author":"Ho","year":"2021","journal-title":"J Endocr Soc"},{"key":"2026080501512697700_noag113-B2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO classification of pituitary tumors","volume":"33","author":"Asa","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026080501512697700_noag113-B3","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/cncr.20412","article-title":"The prevalence of pituitary adenomas: a systematic review","volume":"101","author":"Ezzat","year":"2004","journal-title":"Cancer."},{"key":"2026080501512697700_noag113-B4","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1007\/s12022-017-9498-z","article-title":"Overview of the 2017 WHO classification of pituitary tumors","volume":"28","author":"Mete","year":"2017","journal-title":"Endocr. Pathol"},{"key":"2026080501512697700_noag113-B5","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/EJE-17-0796","article-title":"European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas","volume":"178","author":"Raverot","year":"2018","journal-title":"Eur. J. Endocrinol"},{"key":"2026080501512697700_noag113-B6","doi-asserted-by":"publisher","first-page":"3717","DOI":"10.3390\/ijms26083717","article-title":"A brief overview of molecular biology in pituitary adenomas with a focus on aggressive lesions","volume":"26","author":"Tataranu","year":"2025","journal-title":"Int J Mol Sci"},{"key":"2026080501512697700_noag113-B7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1159\/000549316","article-title":"Radiotherapeutic strategies and advances in the management of pituitary adenomas","volume":"116","author":"Almeida","year":"2026","journal-title":"Neuroendocrinology."},{"key":"2026080501512697700_noag113-B8","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.ecl.2014.10.008","article-title":"Invasive, atypical and aggressive pituitary adenomas and carcinomas","volume":"44","author":"Sav","year":"2015","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2026080501512697700_noag113-B9","doi-asserted-by":"publisher","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"Elife."},{"key":"2026080501512697700_noag113-B10","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1186\/gb-2003-5-1-r1","article-title":"MicroRNA targets in Drosophila","volume":"5","author":"Enright","year":"2003","journal-title":"Genome Biol"},{"key":"2026080501512697700_noag113-B11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/nar\/gkr688","article-title":"miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades","volume":"40","author":"Friedl\u00e4nder","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2026080501512697700_noag113-B12","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1038\/ng2135","article-title":"The role of site accessibility in microRNA target recognition","volume":"39","author":"Kertesz","year":"2007","journal-title":"Nat Genet"},{"key":"2026080501512697700_noag113-B13","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nrg.2016.20","article-title":"Endogenous microRNA sponges: evidence and controversy","volume":"17","author":"Thomson","year":"2016","journal-title":"Nat Rev Genet"},{"key":"2026080501512697700_noag113-B14","doi-asserted-by":"publisher","first-page":"W22","DOI":"10.1093\/nar\/gks554","article-title":"PsRobot: a web-based plant small RNA meta-analysis toolbox","volume":"40","author":"Wu","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2026080501512697700_noag113-B15","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"2026080501512697700_noag113-B16","doi-asserted-by":"publisher","first-page":"W203","DOI":"10.1093\/nar\/gkaf365","article-title":"Cytoscape web: bringing network biology to the browser","volume":"53","author":"Ono","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"2026080501512697700_noag113-B17","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13073-023-01267-3","article-title":"Single-cell transcriptomic analysis reveals tumor cell heterogeneity and immune microenvironment features of pituitary neuroendocrine tumors","volume":"16","author":"Yan","year":"2024","journal-title":"Genome Med"},{"key":"2026080501512697700_noag113-B18","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2026080501512697700_noag113-B19","doi-asserted-by":"publisher","first-page":"5233","DOI":"10.1038\/s41598-019-41695-z","article-title":"From Louvain to Leiden: guaranteeing well-connected communities","volume":"9","author":"Traag","year":"2019","journal-title":"Sci. Rep"},{"key":"2026080501512697700_noag113-B20","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2202\/1544-6115.1128","article-title":"A general framework for weighted gene co-expression network analysis","volume":"4","author":"Zhang","year":"2005","journal-title":"Stat Appl Genet Mol Biol"},{"key":"2026080501512697700_noag113-B21","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/0006-8993(96)00167-9","article-title":"Cloning of human neuronatin gene and its localization to chromosome-20q11.2\u201312: the deduced protein is a novel \u2018Proteolipid\u2019","volume":"723","author":"Dou","year":"1996","journal-title":"Brain Res"},{"key":"2026080501512697700_noag113-B22","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/s00441-015-2325-2","article-title":"Expression studies of neuronatin in prenatal and postnatal rat pituitary","volume":"364","author":"Kanno","year":"2016","journal-title":"Cell Tissue Res"},{"key":"2026080501512697700_noag113-B23","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.jgg.2018.01.003","article-title":"Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment","volume":"45","author":"Piser\u00e0","year":"2018","journal-title":"J Genet Genomics."},{"key":"2026080501512697700_noag113-B24","doi-asserted-by":"publisher","first-page":"281","DOI":"10.3390\/ijms23010281","article-title":"Fidelity of cotranslational protein targeting to the endoplasmic reticulum","volume":"23","author":"Hsieh","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026080501512697700_noag113-B25","doi-asserted-by":"publisher","first-page":"e158-e158","DOI":"10.1038\/oncsis.2015.18","article-title":"Metformin induces ER stress-dependent apoptosis through miR-708-5p\/NNAT pathway in prostate cancer","volume":"4","author":"Yang","year":"2015","journal-title":"Oncogenesis."},{"key":"2026080501512697700_noag113-B26","doi-asserted-by":"publisher","first-page":"2121","DOI":"10.1038\/s44319-025-00410-y","article-title":"miR-708-5p is elevated in bipolar patients and can induce mood disorder-associated behavior in mice","volume":"26","author":"Gilardi","year":"2025","journal-title":"EMBO Rep"},{"key":"2026080501512697700_noag113-B27","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1002\/jcp.25498","article-title":"Neuronatin protein in health and disease: neuronatin protein in health and disease","volume":"232","author":"Pitale","year":"2017","journal-title":"J Cell Physiol"},{"key":"2026080501512697700_noag113-B28","doi-asserted-by":"publisher","first-page":"e24879","DOI":"10.1371\/journal.pone.0024879","article-title":"Functional characterization of the dendritically localized mRNA neuronatin in hippocampal neurons","volume":"6","author":"Oyang","year":"2011","journal-title":"PLoS One."},{"key":"2026080501512697700_noag113-B29","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.3390\/nu15163657","article-title":"Circulating neuronatin levels are positively associated with BMI and body fat mass but not with psychological parameters","volume":"15","author":"Rudolph","year":"2023","journal-title":"Nutrients."},{"key":"2026080501512697700_noag113-B30","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1002\/ddr.22062","article-title":"Tilianin alleviates lipid deposition and fibrosis in mice with nonalcoholic steatohepatitis by activating the PPAR\u03b1\/Nnat axis","volume":"84","author":"Ke","year":"2023","journal-title":"Drug Dev Res"},{"key":"2026080501512697700_noag113-B31","doi-asserted-by":"publisher","first-page":"17571","DOI":"10.1038\/s41598-021-96278-8","article-title":"Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity","volume":"11","author":"Cimino","year":"2021","journal-title":"Sci Rep"},{"key":"2026080501512697700_noag113-B32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.molmet.2018.09.001","article-title":"Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2\/Sv mice","volume":"18","author":"Millership","year":"2018","journal-title":"Mol. Metab"},{"key":"2026080501512697700_noag113-B33","doi-asserted-by":"publisher","first-page":"3369","DOI":"10.1172\/JCI120115","article-title":"Neuronatin regulates pancreatic \u03b2 cell insulin content and secretion","volume":"128","author":"Millership","year":"2018","journal-title":"J Clin Invest"},{"key":"2026080501512697700_noag113-B34","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.2337\/diabetes.54.4.1064","article-title":"Neuronatin, a downstream target of BETA2\/NeuroD1 in the pancreas, is involved in Glucose-Mediated insulin secretion","volume":"54","author":"Chu","year":"2005","journal-title":"Diabetes."},{"key":"2026080501512697700_noag113-B35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s00428-017-2154-7","article-title":"High neuronatin (NNAT) expression is associated with poor outcome in breast cancer","volume":"471","author":"Nass","year":"2017","journal-title":"Virchows Arch"},{"key":"2026080501512697700_noag113-B36","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1097\/JTO.0b013e318145af5e","article-title":"Neuronatin expression and its clinicopathological significance in pulmonary non-small cell carcinoma","volume":"2","author":"Uchihara","year":"2007","journal-title":"J. Thorac. Oncol"},{"key":"2026080501512697700_noag113-B37","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1006\/geno.1996.0195","article-title":"Structure and organization of the human neuronatin gene","volume":"33","author":"Dou","year":"1996","journal-title":"Genomics."},{"key":"2026080501512697700_noag113-B38","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.bbrc.2005.09.078","article-title":"Ectopic expression of neuronatin potentiates adipogenesis through enhanced phosphorylation of cAMP-response element-binding protein in 3T3-L1 cells","volume":"337","author":"Suh","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2026080501512697700_noag113-B39","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/j.cellsig.2008.01.005","article-title":"Crucial roles of neuronatin in insulin secretion and high glucose-induced apoptosis in pancreatic \u03b2-cells","volume":"20","author":"Joe","year":"2008","journal-title":"Cell. Signal"},{"key":"2026080501512697700_noag113-B40","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1002\/stem.530","article-title":"Neuronatin promotes neural lineage in ESCs via Ca2+ signaling","volume":"28","author":"Lin","year":"2010","journal-title":"Stem Cells."},{"key":"2026080501512697700_noag113-B41","doi-asserted-by":"publisher","first-page":"101679","DOI":"10.1016\/j.molmet.2023.101679","article-title":"Regulation of beige adipocyte thermogenesis by the cold-repressed ER protein NNAT","volume":"69","author":"Choi","year":"2023","journal-title":"Mol Metab"},{"key":"2026080501512697700_noag113-B42","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.jconrel.2024.10.039","article-title":"Nanoparticle-mediated synergistic disruption of tumor innervation and redox homeostasis for potent antineoplastic therapy","volume":"376","author":"He","year":"2024","journal-title":"J Control Release."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noag113\/68363891\/noag113.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/28\/8\/1953\/68363891\/noag113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/28\/8\/1953\/68363891\/noag113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:51:38Z","timestamp":1785909098000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/28\/8\/1953\/8690188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,5,21]]},"published-print":{"date-parts":[[2026,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noag113","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,5,21]]}}}