{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:27:53Z","timestamp":1786343273351,"version":"build-2736575974"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"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. Med."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the mechanism by which Notch1 induces M2 polarization of tumor-associated macrophages (TAMs) through regulation of the YAP\/EZH2\/JMJD3\/PTEN\/FOXD1\/galectin-3\/CD47 signaling pathway and its role in non-small cell lung cancer (NSCLC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bioinformatics analysis was utilized to identify Notch1 and M2 polarization-related genes.\n                      <jats:italic>In vivo<\/jats:italic>\n                      tumor progression was assessed using a subcutaneous xenograft tumor model in nude mice.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments employed Western blot to detect relevant protein expression levels, real-time quantitative polymerase chain reaction (RT-qPCR) to detect IL-1\u03b2, TNF-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      , arginase-1, and Cathepsin B\/K, flow cytometry to detect apoptosis and proliferation, plate colony formation assay to detect clonogenic ability, scratch assay to detect cell migration, and Transwell assay to detect cell invasion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In NSCLC, tumor cells activate Notch1 signaling through Jagged-1, triggering NICD\/RBP-J-mediated YAP synthesis and activation. Activated YAP enhances Jagged-1 expression through positive feedback, forming a Notch1\/YAP signal amplification loop, and inhibits PTEN expression by activating EZH2 (in antagonism with JMJD3). PTEN deficiency relieves dual inhibition of the PI3K\/Hippo pathways, leading to sustained YAP activation, which subsequently drives FOXD1 transcription and downstream expression of galectin-3 and C-MYC. C-MYC not only promotes tumor proliferation and invasion but also induces high expression of the immune checkpoint molecule CD47. CD47 binds to SIRP\u03b1 on the surface of tumor-associated TAMs, blocking M1 polarization, driving M2 polarization, and activating the STAT3\/PD-L1 axis. PD-L1 further induces endoplasmic reticulum stress (ERS) and promotes Cathepsin K\/B expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Notch1 induces M2 polarization of TAMs by activating the YAP\/EZH2\/JMJD3\/PTEN\/FOXD1\/galectin-3\/CD47 signaling pathway, thereby promoting NSCLC progression. This study provides important clues for understanding the molecular mechanisms of NSCLC and identifying potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1801942","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:32Z","timestamp":1786339832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Notch-1 induces M2 polarization of tumor-associated macrophages via the YAP\/EZH2\/FOXD1\/CD47 signaling axis, thereby driving non-small cell lung cancer progression"],"prefix":"10.3389","volume":"13","author":[{"given":"Lei","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Cangzhou Central Hospital","place":["Cangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Cangzhou Central Hospital","place":["Cangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meifang","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Cangzhou Central Hospital","place":["Cangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Science and Technology Experiment Center, Cangzhou Medical College","place":["Cangzhou, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"11701","DOI":"10.3390\/ijms222111701","article-title":"Histone modification in NSCLC: molecular mechanisms and therapeutic targets","volume":"22","author":"Bajbouj","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"102545","DOI":"10.1016\/j.ctrv.2023.102545","article-title":"Immunotherapy-based combinations in metastatic NSCLC","volume":"116","author":"Desai","year":"2023","journal-title":"Cancer Treat Rev"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1002\/cac2.12345","article-title":"Tumor-associated macrophages in liver cancer: from mechanisms to therapy","volume":"42","author":"Cheng","year":"2022","journal-title":"Cancer Commun"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"6995","DOI":"10.3390\/ijms22136995","article-title":"Macrophage polarization states in the tumor microenvironment","volume":"22","author":"Boutilier","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1210\/er.2016-1002","article-title":"Notch Signaling and the skeleton","volume":"37","author":"Zanotti","year":"2016","journal-title":"Endocr Rev"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1158\/2326-6066.CIR-23-0037","article-title":"Notch Signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer","volume":"12","author":"Yan","year":"2024","journal-title":"Cancer Immunol Res"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"111133","DOI":"10.1016\/j.isci.2024.111133","article-title":"Intra-tumoral YAP and TAZ heterogeneity drives collective NSCLC invasion that is targeted by SUMOylation inhibitor TAK-981","volume":"27","author":"Sharma","year":"2024","journal-title":"iScience"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/j.jcmgh.2023.01.002","article-title":"Targeting Notch1-YAP circuit reprograms macrophage polarization and alleviates acute liver injury in mice","volume":"15","author":"Yang","year":"2023","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s41419-023-05782-4","article-title":"Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization","volume":"14","author":"Zhou","year":"2023","journal-title":"Cell Death Dis"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2706","DOI":"10.7150\/thno.48679","article-title":"Histone demethylase JMJD3 protects against renal fibrosis by suppressing TGF\u03b2 and notch signaling and preserving PTEN expression","volume":"11","author":"Yu","year":"2021","journal-title":"Theranostics"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"154902","DOI":"10.1016\/j.prp.2023.154902","article-title":"New emerging targets in osteosarcoma therapy: PTEN and PI3K\/Akt crosstalk in carcinogenesis","volume":"251","author":"Sadrkhanloo","year":"2023","journal-title":"Pathol Res Pract"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"101633","DOI":"10.1016\/j.tranon.2023.101633","article-title":"Endothelial plasticity across PTEN and hippo pathways: a complex hormetic rheostat modulated by extracellular vesicles","volume":"31","author":"Orozco-Garc\u00eda","year":"2023","journal-title":"Transl Oncol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"966","DOI":"10.2174\/0109298665265642231020043809","article-title":"MicroRNA3650 promotes gastric Cancer proliferation and migration through the PTEN\/PI3K-AKT-mTOR and hippo pathways","volume":"30","author":"Yang","year":"2023","journal-title":"Protein Pept Lett"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3281","DOI":"10.7150\/ijbs.60782","article-title":"CD47\/SIRP\u03b1 pathway mediates cancer immune escape and immunotherapy","volume":"17","author":"Jia","year":"2021","journal-title":"Int J Biol Sci"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"3726","DOI":"10.1158\/0008-5472.CAN-23-0783","article-title":"Galectin-3 cooperates with CD47 to suppress phagocytosis and T-cell immunity in gastric Cancer peritoneal metastases","volume":"83","author":"Fan","year":"2023","journal-title":"Cancer Res"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e3000201","DOI":"10.1371\/journal.pbio.3000201","article-title":"Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis","volume":"17","author":"Fu","year":"2019","journal-title":"PLoS Biol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.3390\/cancers11121897","article-title":"FOXD1 and Gal-3 form a positive regulatory loop to regulate lung cancer aggressiveness","volume":"11","author":"Li","year":"2019","journal-title":"Cancers"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.semradonc.2014.11.006","article-title":"Hypoxia as a cause of treatment failure in non\u2013small cell carcinoma of the lung","volume":"25","author":"Brustugun","year":"2015","journal-title":"Semin Radiat Oncol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/s41419-023-06345-3","article-title":"Hypoxia-induced activation of NDR2 underlies brain metastases from non-small cell lung cancer","volume":"14","author":"Levallet","year":"2023","journal-title":"Cell Death Dis"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41580-018-0086-y","article-title":"Hippo\u2013YAP\/TAZ signalling in organ regeneration and regenerative medicine","volume":"20","author":"Moya","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41420-024-02216-8","article-title":"The oncogenic axis YAP\/MYC\/EZH2 impairs PTEN tumor suppression activity enhancing lung tumorigenicity","volume":"10","author":"Lo Sardo","year":"2024","journal-title":"Cell Death Discov"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/jcmm.15997","article-title":"G protein-coupled oestrogen receptor promotes cell growth of non-small cell lung cancer cells via YAP1\/QKI\/circNOTCH1\/m6A methylated NOTCH1 signalling","volume":"25","author":"Shen","year":"2021","journal-title":"J Cell Mol Med"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"365","DOI":"10.30699\/IJP.2024.2013339.3184","article-title":"Role of Notch1 signaling pathway in small cell lung carcinoma","volume":"19","author":"Charbat","year":"2024","journal-title":"Iran J Pathol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1801942\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:33Z","timestamp":1786339833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1801942\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":23,"alternative-id":["10.3389\/fmed.2026.1801942"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1801942","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"article-number":"1801942"}}