{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:03:46Z","timestamp":1788455026264,"version":"build-2803163510"},"reference-count":71,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007834","name":"Natural Science Foundation of Ningbo Municipality","doi-asserted-by":"publisher","award":["2023J404"],"award-info":[{"award-number":["2023J404"]}],"id":[{"id":"10.13039\/100007834","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82074101"],"award-info":[{"award-number":["82074101"]}],"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":["82274297"],"award-info":[{"award-number":["82274297"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Exosomes critically regulate pre\u2010metastatic niche formation and tumor metastasis in colorectal cancer (CRC). Our prior research revealed that RALY, an RNA\u2010binding protein, regulates exosome biogenesis during CRC metastasis. Furthermore, we recently demonstrated that Astragaloside IV (ASIV) inhibits CRC metastasis by suppressing tumor exosome release in a dose\u2010dependent manner. However, its pharmacological targets and mechanisms remain unclear. Exosomes derived from MC38 cells with\/without ASIV treated were characterized and quantified using NanoSight analysis, transmission electron microscopy (TEM), and Western blot (WB). The regulatory roles of ASIV and RALY in exosome biogenesis were assessed by immunofluorescence (IF) staining. RNA immunoprecipitation (RIP) and co\u2010immunoprecipitation (co\u2010IP) assays identified RALY\u2010interacting partners, while methylated RIP measured m6A levels on PLD2 transcripts. Liver metastasis model in mice was established by injecting MC38 or shRALY single cell suspension into the spleen of mice to observe the effect of ASIV on CRC liver metastasis. Limited Proteolysis\u2010Small Molecule Mapping (LiP\u2010SMap) screened ASIV\u2010binding proteins, followed by molecular docking and cellular thermal shift assays (CETSA) to confirm direct target interactions. ASIV reduced RALY levels in CRC cells, inhibiting exosome release. Mechanistically, ASIV disrupted the RALY\u2010PLD2 interaction, regulating exosome biogenesis. TERT was identified as a direct ASIV target, blocking RALY transcription due to its nuclear translocation function. In\u00a0vivo experiments showed that ASIV attenuated liver metastasis by down\u2010regulating RALY and inhibiting exosome release through disrupting RBM15b\u2010driven m6A modification of PLD2. Our findings revealed that ASIV mitigated CRC liver metastasis by downregulating the RALY\/PLD2 axis, which was instrumental in exosome biogenesis. This discovery furnished compelling experimental evidence supporting the clinical utility of ASIV in combating CRC metastasis. Significantly, our research underscored the substantial advantages of targeting exosome\u2010mediated metastasis, thereby highlighting the necessity for subsequent clinical validation.<\/jats:p>","DOI":"10.1002\/ptr.70154","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T06:55:25Z","timestamp":1766732125000},"page":"681-700","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Astragaloside\n                    <scp>IV<\/scp>\n                    Alleviates Colorectal Cancer Metastases by Regulating\n                    <scp>RALY<\/scp>\n                    \/\n                    <scp>PLD2<\/scp>\n                    Axis and Inhibiting Tumoral Exosome Biogenesis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0720-0420","authenticated-orcid":false,"given":"Ling","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"Department of Medical Oncology &amp; Cancer Institute of Integrative Medicine Shuguang Hospital, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3449-4200","authenticated-orcid":false,"given":"Xin\u2010nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine Putuo Hospital, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2513-5329","authenticated-orcid":false,"given":"Yun\u2010zhou","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology &amp; Cancer Institute of Integrative Medicine Shuguang Hospital, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8858-7286","authenticated-orcid":false,"given":"Lei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology &amp; Cancer Institute of Integrative Medicine Shuguang Hospital, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-1478","authenticated-orcid":false,"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1899-0204","authenticated-orcid":false,"given":"Qing","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology &amp; Cancer Institute of Integrative Medicine Shuguang Hospital, Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4565-7693","authenticated-orcid":false,"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Liver Disease Department of Integrative Medicine  Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.06.006"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.0106"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165919"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010022\u201001511\u20101"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.11.003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13079"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154903"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2020.11.015"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4477"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010021\u201000730\u20101"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202405997"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215751"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112230"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15756"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.28288"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.34172\/bi.2022.23489"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.138"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15871"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj7002"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081883"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11020187"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.06.082"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010024\u201002991\u20103"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010021\u201001312\u2010y"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2021.4849"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.178"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202001191"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.97397"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010019\u20100805\u20107"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010024\u201003039\u20108"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12311"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010019\u20100963\u20109"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.02.023"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010021\u201001485\u20106"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010022\u201001305\u20104"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010019\u20100390\u2010y"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010022\u201005336\u20100"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u20100234\u2010z"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.381"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/02648725.2023.2194087"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13485"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155683"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgy115"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202209084"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2023.03.022"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.639898"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.05.048"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.01.003"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102020\u2010320652"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.740565"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476\u20104598\u201010\u2010145"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.03.127"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2023.11.029"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17300"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000001666"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422\u2010020\u201000409\u20101"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21060777"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010024\u201001938\u2010z"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010020\u201000218\u20109"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1065505"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010020\u201001208\u20103"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11121946"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2017.01.006"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.6070"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010022\u201004506\u20104"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102492"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2014.47.1.284"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.133112"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e31450"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010024\u201002086\u20109"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70154","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70154","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70154","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T12:31:19Z","timestamp":1770381079000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,25]]},"references-count":71,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/ptr.70154"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70154","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,25]]},"assertion":[{"value":"2025-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}