{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:40:15Z","timestamp":1792183215051,"version":"4.4.0"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100012899","name":"Lanzhou University","doi-asserted-by":"publisher","award":["561119203"],"award-info":[{"award-number":["561119203"]}],"id":[{"id":"10.13039\/100012899","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pigment Cell Melanoma Res"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Melanoma is an aggressive malignant tumor with a poor prognosis. Vemurafenib (PLX4032, vem) is applied to specifically treat BRAF V600E\u2010mutated melanoma patients. However, prolonged usage of vem makes patients resistant to the drug and finally leads to clinical failure. We previously tested the combination regimen of tubulin inhibitor VERU\u2010111 with vem, as well as USP14 selective inhibitor b\u2010AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in\u00a0vitro and in\u00a0vivo. Most importantly, we discovered that vem\u2010resistant melanoma cell lines highly expressed E3 ligase SKP2 and DUB enzyme USP14, and we have demonstrated that USP14 directly interacts and stabilizes SKP2, which contributes to vem resistance. These works give us a clue that USP14 might be a promising target to overcome vem resistance in melanoma. MitoCur\u20101 is a curcumin derivative, which was originally designed to specifically target tumor mitochondria inducing redox imbalance, thereby promoting tumor cell death. In this study, we have demonstrated that it can work as a novel USP14 inhibitor, and thus bears great potential in providing an anti\u2010tumor effect and sensitizing vem\u2010resistant cells by inducing ferroptosis in melanoma. Application of MitoCur\u20101 dramatically induces USP14 inhibition and inactivation of GPX4 enzyme, meanwhile, increases the depletion of GSH and decreases SLC7A11 expression level. As a result, ferrous iron\u2010dependent lipid ROS accumulated in the cell, inducing ferroptosis, thus sensitizes the vem\u2010resistant melanoma cell. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur\u20101, therefore, we conclude that MitoCur\u20101 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.<\/jats:p>","DOI":"10.1111\/pcmr.13150","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T22:49:40Z","timestamp":1700606980000},"page":"316-328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["MitoCur\u20101 induces ferroptosis to reverse vemurafenib resistance in melanoma through inhibition of USP14"],"prefix":"10.1111","volume":"37","author":[{"given":"Gege","family":"Li","sequence":"first","affiliation":[{"name":"School of Public Health, Institute of Toxicology Lanzhou University Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changlong","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Public Health, Institute of Toxicology Lanzhou University Lanzhou 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