{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T03:07:36Z","timestamp":1783825656509,"version":"3.55.0"},"reference-count":65,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2021J01695"],"award-info":[{"award-number":["2021J01695"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2025J01681"],"award-info":[{"award-number":["2025J01681"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Tyrosine kinase inhibitors (TKIs), such as sorafenib, lenvatinib, and regorafenib, serve as the mainstay targeted therapies for advanced hepatocellular carcinoma (HCC), yet resistance severely limits their clinical benefits. This study aimed to elucidate the role of CXCR4 in promoting vasculogenic mimicry (VM) to drive TKI resistance and to explore the natural chalcone flavokawain A (FKA) as a novel CXCR4\u2010targeting agent to overcome this challenge. Utilizing comprehensive experimental approaches\u2014including transcriptome sequencing, MTT, transwell and 3D\u2010tubule formation assays, western blotting, molecular docking, cellular thermal shift assay (CETSA), and a subcutaneous xenograft model\u2014we confirmed that sorafenib (0\u20138\u2009\u03bcM) elevated CXCR4, consistent with our prior reports, and first revealed a similar upregulation occurred following exposure to lenvatinib (0\u201310\u2009\u03bcM) and regorafenib (0\u20132\u2009\u03bcM), with CXCR4 further enriched in TKI\u2010resistant cells. CXCR4 overexpression promoted VM formation and reduced TKI sensitivity, while its knockdown suppressed VM and restored TKI responsiveness. Mechanistically, CXCR4 facilitated VM through the Snail\/E\u2010cadherin\/Vimentin and VE\u2010cadherin\/EphA2\/MMP\u201014\/MMP\u20102\/Laminin5\u03b32 pathways. TKI\u2010resistant cells with upregulated CXCR4 exhibited a pronounced VM phenotype, including enhanced proliferation, migration, invasion, and VM. CXCR4 depletion attenuated these VM hallmarks and resensitized resistant cells to TKIs. FKA disrupted the VM phenotype by directly targeting CXCR4, and synergized with TKI to inhibit HCC growth in\u00a0vitro and in\u00a0vivo, with its efficacy being CXCR4\u2010dependent. Collectively, our findings suggest that CXCR4 promotes VM to drive TKI resistance and reveal that FKA, as a potential CXCR4 inhibitor, represents a promising therapeutic strategy in combination with TKIs to overcome resistance in HCC.<\/jats:p>","DOI":"10.1002\/ptr.70360","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:21:36Z","timestamp":1777454496000},"page":"4206-4227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Flavokawain A Targets\n                    <scp>CXCR4<\/scp>\n                    \u2010Mediated Vasculogenic Mimicry to Reverse Hepatocellular Carcinoma Resistance to Tyrosine Kinase Inhibitors"],"prefix":"10.1002","volume":"40","author":[{"given":"Ning","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fujian Key Laboratory of Natural Medicine Pharmacology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fujian Key Laboratory of Natural Medicine Pharmacology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fujian Key Laboratory of Natural Medicine Pharmacology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fujian Key Laboratory of Natural Medicine Pharmacology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayixuwake","family":"Bahediyaer","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases School of Basic Medical Sciences, Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhen","family":"Su","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases School of Basic Medical Sciences, Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fujian Key Laboratory of Natural Medicine Pharmacology Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-0771","authenticated-orcid":false,"given":"Jichuang","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases School of Basic Medical Sciences, Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14894"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noad076"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2024.02.025"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26790"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27665"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.01.066"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010022\u201001194\u2010y"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010025\u201001739\u20106"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.760330"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401\u2010022\u201001021\u20102"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.07.035"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1194199"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.18673"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010022\u201004576\u20104"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112230"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201021\u20104140"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2022.100849"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201022\u20100963"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2024.0824"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2017.107"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.217472"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003741\u20107"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2025.117305"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S259432"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2019.11069"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2025.189323"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0177335"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010022\u201002500\u20104"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010020\u201000395\u20100"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010024\u201000868\u20100"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002\u20109440(10)65173\u20105"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC\u201019\u20100054"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70018"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326\u20106066.CIR\u201024\u20100324"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2022.188790"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010021\u201003730\u20108"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2014.102"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001963\u20105"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.652007"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010024\u201001549\u20102"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5110"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2015433118"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2011.24"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010019\u20101475\u20106"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100809"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.01.041"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.12.010"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2020.113288"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17300"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2022.01.003"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010020\u201001288\u20101"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154687"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175981"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215944"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201016\u20102131"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.09.012"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.44789"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.23279"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.3724\/abbs.2024058"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2021.153740"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201032428\u20109"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010019\u20101216\u2010x"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105507"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010020\u201001029\u20103"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468\u20101253(24)00247\u20104"}],"container-title":["Phytotherapy Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70360","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ptr.70360","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ptr.70360","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:18:04Z","timestamp":1783448284000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ptr.70360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":65,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1002\/ptr.70360"],"URL":"https:\/\/doi.org\/10.1002\/ptr.70360","archive":["Portico"],"relation":{},"ISSN":["0951-418X","1099-1573"],"issn-type":[{"value":"0951-418X","type":"print"},{"value":"1099-1573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"assertion":[{"value":"2025-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}