{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T21:23:59Z","timestamp":1783113839786,"version":"3.54.6"},"reference-count":32,"publisher":"Wiley","issue":"34","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62472095"],"award-info":[{"award-number":["62472095"]}],"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":["62172213"],"award-info":[{"award-number":["62172213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2025J01088"],"award-info":[{"award-number":["2025J01088"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Triple\u2010negative breast cancer (TNBC) exhibits addiction to chronic endoplasmic reticulum (ER) stress, which sustains an aggressive metastatic phenotype through activation of the unfolded protein response (UPR). Here, we identify a previously unrecognized \u201cER\u2010stress addiction\u201d axis in which the Hippo pathway effector TEAD4 directly transcriptionally upregulates the ER chaperone PDIA4. We further demonstrate that this axis can be pharmacologically targeted by a natural polysaccharide.\n                    <jats:italic>Tetrastigma hemsleyanum<\/jats:italic>\n                    polysaccharide (THP) selectively activates the Hippo kinase cascade, leading to YAP phosphorylation, cytoplasmic sequestration, and subsequent degradation. This cascade attenuates YAP\/TEAD4 interaction and abolishes TEAD4 DNA\u2010binding activity. Moreover, THP downregulates TEAD4 expression. These combined effects drive transcriptional suppression of PDIA4, catastrophic disruption of ER proteostasis, and ultimately lethal ER stress in TNBC cells. Functionally, THP inhibits migration, invasion, angiogenesis, and intracellular Ca\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    flux in vitro, and\u2014importantly\u2014blocks metastasis in patient\u2010derived organoids, zebrafish xenografts, and two syngeneic mouse models at non\u2010toxic doses. Multi\u2010omics analyses and rescue assays confirm the TEAD4\u2010PDIA4 axis as the core functional module. Our findings establish THP as a first\u2010in\u2010class, natural\u2010product\u2010based therapeutic that disrupts ER\u2010stress addiction in metastatic TNBC by targeting the Hippo\u2010YAP\/TEAD4\u2010PDIA4 axis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519006","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T19:01:23Z","timestamp":1775156483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Tetrastigma Hemsleyanum<\/i>\n                    Polysaccharide Suppresses Triple\u2010Negative Breast Cancer by Disrupting the Hippo\u2010YAP\/TEAD4\u2010PDIA4 Axis and Endoplasmic Reticulum Stress Adaptation"],"prefix":"10.1002","volume":"13","author":[{"given":"Yini","family":"Shang","sequence":"first","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Si","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youxue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Harbin Medical University Cancer Hospital  Harbin Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Harbin Medical University Cancer Hospital  Harbin Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaixi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery Harbin Medical University Cancer Hospital  Harbin Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medical Technology and Information Engineering Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmeng","family":"Su","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"},{"name":"Department of Bioinformatics Fujian Key Laboratory of Medical Bioinformatics Institute of Precision Medicine School of Medical Technology and Engineering Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhishan","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Medical Technology and Information Engineering Zhejiang Chinese Medical University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6715-2944","authenticated-orcid":false,"given":"Lihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2023.07.029"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116439"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010023\u201001963\u20105"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23061445"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.11.155"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.112663"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113247"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1FO02588K"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.133424"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010025\u201008356\u20108"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010025\u201001446\u20102"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010026\u201003246\u20101"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adx2532"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u20100250\u2010z"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010025\u201003606\u20107"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010023\u201002640\u20101"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acr.2023.06.001"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-10036-8"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.70431"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010025\u201007098\u20107"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201005719\u2010x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058\u2010023\u201001758\u20106"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40001\u2010025\u201002500\u2010y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010025\u201002506\u20109"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8060600"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.add0960"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000001687"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad042"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1049"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5c00527"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20150233"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202519006","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202519006","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202519006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T20:53:37Z","timestamp":1783112017000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202519006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":32,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/advs.202519006"],"URL":"https:\/\/doi.org\/10.1002\/advs.202519006","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"assertion":[{"value":"2025-09-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e19006"}}