{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:46:52Z","timestamp":1789343212869,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFE0213800"],"award-info":[{"award-number":["2024YFE0213800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intrahepatic cholangiocarcinoma (ICC) exhibits poor prognosis and limited therapeutic options. Ferroptosis represents a promising therapeutic strategy, yet resistance mechanisms remain poorly understood. This study investigated the role of mucin 1 (MUC1) in regulating ferroptosis sensitivity in ICC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bioinformatic analyses of GEO and TCGA datasets identified ferroptosis\u2010related factors in ICC. MUC1 expression was validated in ICC cell lines and clinical specimens. Ferroptosis sensitivity was assessed through RSL3\u2010induced cell death assays, lipid peroxidation measurements, and iron detection. Mechanistic studies employed immunoprecipitation\u2010mass spectrometry, co\u2010immunoprecipitation, kinase assays, and deubiquitination assays. In vivo efficacy was evaluated using subcutaneous tumor models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MUC1 was identified as a critical ferroptosis suppressor in ICC. MUC1 overexpression conferred RSL3 resistance by inhibiting lipid peroxidation and reducing ferrous iron accumulation, independent of the GPX4\u2010glutathione pathway. Mechanistically, MUC1 recruited Src kinase, which phosphorylated deubiquitinating enzyme ubiquitin\u2010specific protease 10 (USP10) at tyrosines 359 and 364, enhancing ferroptosis suppressor protein 1 (FSP1) deubiquitination at lysine 246 and stabilizing FSP1 protein. Concurrently, Src phosphorylated N\u2010myristoyltransferase 1 (NMT1) at tyrosine 41, augmenting FSP1 membrane localization through myristoylation. This dual mechanism potentiated the FSP1\u2010 coenzyme Q10 (CoQ10) antioxidant system. MUC1 knockdown significantly enhanced ferroptotic sensitivity in vitro and suppressed tumor growth in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>MUC1 orchestrates ferroptosis resistance in ICC through the Src\u2010USP10\/NMT1\u2010FSP1 axis. Targeting this signaling cascade represents a potential therapeutic strategy for overcoming ferroptosis resistance in ICC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>MUC1 suppresses ferroptosis in ICC via Src\u2010mediated post\u2010translational modifications.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Src phosphorylation of USP10 stabilizes FSP1 by removing K48\u2010linked polyubiquitin.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Src activates NMT1 to enhance FSP1 myristoylation and membrane localization.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70495","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T03:30:31Z","timestamp":1760067031000},"source":"Crossref","is-referenced-by-count":5,"title":["MUC1 drives ferroptosis resistance in ICC via Src\u2010mediated FSP1 deubiquitination and myristoylation"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3174-4825","authenticated-orcid":false,"given":"Yuqiao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixiang","family":"Han","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qichao","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanlie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boshi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Endemic Disease Control Chinese Center for Disease Control and Prevention Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery The 2nd Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21759"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.03.010"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2020.04.067"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000531458"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u201000324\u20108"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.03.022"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010020\u201000462\u20100"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010025\u201007571\u20107"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2024.8851"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.003"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010024\u201002009\u20108"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238\u2010021\u201000841\u2010y"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.115015"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.155135"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010022\u201002567\u2010z"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010022\u201001096\u20108"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115701"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434\u2010024\u201016065\u20103"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.156303"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201035795\u20108"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201902074"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202416360"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2170960"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201038753\u20106"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126567"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2017.03.003"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2014.02.007"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.0c01249"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2021.5248"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.4251\/wjgo.v8.i10.725"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101705\u20102"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010020\u20100356\u2010y"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114366"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010022\u201001008\u2010w"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001969\u2010z"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.54113"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1810918"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422\u2010020\u201000441\u20101"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010021\u201002231\u2010x"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010024\u201002046\u20103"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303807"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103176"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70495","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T19:01:22Z","timestamp":1764010882000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70495"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/ctm2.70495"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70495","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]},"article-number":"e70495"}}