{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:53:12Z","timestamp":1788403992727,"version":"build-2803163510"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014857","name":"National Natural Science Foundation of China-Guangdong Joint Fund","doi-asserted-by":"publisher","award":["82473367 82122047 82072633 82403136 82330095 81920108025 82203044 82003171 and 82303000"],"award-info":[{"award-number":["82473367 82122047 82072633 82403136 82330095 81920108025 82203044 82003171 and 82303000"]}],"id":[{"id":"10.13039\/501100014857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:p>Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein. Inhibition of MALT1 expression enhances GPX4 ubiquitination-mediated degradation by up-regulating the E3 ubiquitin ligase RC3H1. Using both rescue assays and functional genetic screening, we demonstrate that pharmacologically targeting MALT1 triggers ferroptosis in liver cancer cells. Moreover, we show that targeting MALT1 synergizes with sorafenib or regorafenib to induce ferroptosis across multiple cancer types. These findings elucidate the modulatory effects of the MALT1\u2013RC3H1 axis on GPX4 stability, revealing a molecular mechanism that could be exploited to induce ferroptosis for cancer therapy.<\/jats:p>","DOI":"10.1073\/pnas.2419625121","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T13:42:02Z","timestamp":1735652522000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Deciphering the role of the MALT1\u2013RC3H1 axis in regulating GPX4 protein stability"],"prefix":"10.1073","volume":"122","author":[{"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Liao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2307-3280","authenticated-orcid":false,"given":"Beiping","family":"Miao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"German Cancer Research Center, Division Immune Regulation in Cancer","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Reproduction and Genetics, First Affiliated Hospital of University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Botai","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhui","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Division of Molecular Oncology &amp; Immunology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Fitz","sequence":"additional","affiliation":[{"name":"German Cancer Research Center, Division Immune Regulation in Cancer","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"He","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Shanghai Tenth People\u2019s Hospital, Tongji University, School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangzhi","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Sun","sequence":"additional","affiliation":[{"name":"German Cancer Research Center, Division Immune Regulation in Cancer","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-3423","authenticated-orcid":false,"given":"Ren\u00e9","family":"Bernards","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute","place":["Amsterdam, The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4977-2189","authenticated-orcid":false,"given":"Cun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.010"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00459-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23007"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI166647"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2022.11.003"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.003"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01200-4"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.03.019"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708857"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30207-1"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915745"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.030"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01270-0"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327909"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01133-9"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1687985"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101807"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-023-02117-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2015.09.018"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3008"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03555"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep15660"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.11.003"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01748-9"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24297"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)32453-9"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24148"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02523"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114351"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2021.11.002"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-019-0380-z"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-020-00789-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60421-9"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61900-X"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-021-06301-9"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44228-5"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202301852"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg3049"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00745"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.875320"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(04)00236-9"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-023-00809-7"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022019274"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202206798"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.10.011"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13158"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2419625121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T13:44:24Z","timestamp":1735652664000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2419625121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,31]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,7]]}},"alternative-id":["10.1073\/pnas.2419625121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2419625121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,31]]},"assertion":[{"value":"2024-09-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2419625121"}}