{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:26:44Z","timestamp":1788877604833,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011566","name":"Sidney Kimmel Comprehensive Cancer Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011566","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001391","name":"Whitehall Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001391","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":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Uveal melanoma (UM) is an aggressive intraocular malignancy. Despite effective control of primary tumors, ~50% of UM patients develop metastases, with the liver being the predominant secondary site. BAP1 deficiency, present in ~80% of metastatic UM cases, is strongly associated with increased metastatic risk and poor prognosis. In silico analysis of UM patient samples suggests that reduced BAP1 is linked to enhanced expression of genes involved in fatty acid processing; therefore, we hypothesize that BAP1 deficiency primes UM cells for survival in the hepatic microenvironment by enhancing lipid tolerance and oxidative stress responses. Our findings demonstrate BAP1\u2010mutant UM resist lipotoxicity, whereas BAP1\u2010competent UM exhibit sensitivity due to lipid peroxide accumulation\u2014a hallmark of ferroptotic\u2010like stress, and a response that can be mitigated by ferroptosis inhibition. Using an ex\u00a0vivo liver slice model, we found that disrupting lipid metabolism with atorvastatin, an HMG\u2010CoA reductase inhibitor, reduced tumor burden of BAP1\u2010mutant UM. Moreover, we demonstrate a positive correlation between BAP1 and an epigenetic regulator of lipid homeostasis, ASXL2. Notably, ASXL2 depletion in BAP1\u2010competent UM phenocopies the lipotoxicity resistance observed in BAP1\u2010mutant UM\u2014an effect that may be mediated by altered PPAR expression. This study reveals a novel mechanism linking BAP1 expression to lipid sensitivity via ASXL2, providing insights into liver tropism and potential therapeutic avenues for metastatic uveal melanoma.<\/jats:p>","DOI":"10.1111\/pcmr.70021","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T01:15:13Z","timestamp":1745975713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>BAP1<\/scp> Loss Affords Lipotoxicity Resistance in Uveal Melanoma"],"prefix":"10.1111","volume":"38","author":[{"given":"C. J.","family":"Cunanan","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Amirfallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. B.","family":"Sanders","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. C.","family":"Gallant","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. R.","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. A.","family":"Homer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. S.","family":"El Naggar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. K.","family":"Farnan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"},{"name":"Sidney Kimmel Comprehensive Cancer Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2363-5442","authenticated-orcid":false,"given":"J. L.","family":"Hope","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center  Philadelphia Pennsylvania USA"},{"name":"Department of Microbiology &amp; Immunology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. G.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"},{"name":"Sidney Kimmel Comprehensive Cancer Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Hartsough","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"},{"name":"Sidney Kimmel Comprehensive Cancer Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2018.tb00008.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.04.003"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-21-0657"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp101"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3459"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00714-1"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000425"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06854-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.661553"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0672"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2000.002"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0546-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-148X.2012.00979.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1194472"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304753"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77419"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.05.019"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0158-0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2008.02.007"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000055RR"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2013.02.004"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136215"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12304"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01364-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAT.0b013e32835d0efb"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103485"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.03.009"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4196"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.11.124"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.177816"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2022.100479"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541\u20107786.MCR\u201020\u20100080"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200767001-00002"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092557"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0805"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10292"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-020-02377-x"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2018.12.046"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1170-y"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202052280"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.318436.118"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.7b00028"}],"container-title":["Pigment Cell &amp; Melanoma Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pcmr.70021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T08:22:06Z","timestamp":1749198126000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/pcmr.70021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1111\/pcmr.70021"],"URL":"https:\/\/doi.org\/10.1111\/pcmr.70021","archive":["Portico"],"relation":{},"ISSN":["1755-1471","1755-148X"],"issn-type":[{"value":"1755-1471","type":"print"},{"value":"1755-148X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]},"assertion":[{"value":"2024-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70021"}}