{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:49:32Z","timestamp":1790362172494,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T00:00:00Z","timestamp":1653523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["19K09198"],"award-info":[{"award-number":["19K09198"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["JP\u201016K10576"],"award-info":[{"award-number":["JP\u201016K10576"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The tyrosine kinase inhibitor lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Ferroptosis is a type of cell death characterized by the iron\u2010dependent accumulation of lethal lipid reactive oxygen species (ROS). Nuclear factor erythroid\u2010derived 2\u2010like 2 (Nrf2) protects HCC cells against ferroptosis. However, the mechanism of lenvatinib\u2010induced cytotoxicity and the relationships between lenvatinib resistance and Nrf2 are unclear. Thus, we investigated the relationship between lenvatinib and ferroptosis and clarified the involvement of Nrf2 in lenvatinib\u2010induced cytotoxicity. Cell viability, lipid ROS levels, and protein expression were measured using Hep3B and HuH7 cells treated with lenvatinib or erastin. We examined these variables after silencing fibroblast growth factor receptor\u20104 (FGFR4) or Nrf2 and overexpressing\u2010Nrf2. We immunohistochemically evaluated FGFR4 expression in recurrent lesions after resection and clarified the relationship between FGFR4 expression and lenvatinib efficacy. Lenvatinib suppressed system X\n                    <jats:sub>c<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    (xCT) and glutathione peroxidase 4 (GPX4) expression. Inhibition of the cystine import activity of xCT and GPX4 resulted in the accumulation of lipid ROS. Silencing\u2010FGFR4\u00a0suppressed xCT and GPX4 expression and increased lipid ROS levels. Nrf2\u2010silenced HCC cells displayed sensitivity to lenvatinib and high lipid ROS levels. In contrast, Nrf2\u2010overexpressing HCC cells displayed resistance to lenvatinib and low lipid ROS levels. The efficacy of lenvatinib was significantly lower in recurrent HCC lesions with low\u2010FGFR4 expression than in those with high\u2010FGFR4 expression. Patients with FGFR4\u2010positive HCC displayed significantly longer progression\u2010free survival than those with FGFR4\u2010negative HCC. Lenvatinib induced ferroptosis by inhibiting FGFR4. Nrf2 is involved in the sensitivity of HCC to lenvatinib.\n                  <\/jats:p>","DOI":"10.1111\/cas.15378","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T04:34:02Z","timestamp":1650861242000},"page":"2272-2287","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor\u20104 inhibition in hepatocellular carcinoma"],"prefix":"10.1111","volume":"113","author":[{"given":"Norifumi","family":"Iseda","sequence":"first","affiliation":[{"name":"Department of Surgery and Science Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0382-2520","authenticated-orcid":false,"given":"Shinji","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science Graduate 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