{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:12:39Z","timestamp":1792005159611,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374092"],"award-info":[{"award-number":["82374092"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103967"],"award-info":[{"award-number":["82103967"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["QKHM25H3103"],"award-info":[{"award-number":["QKHM25H3103"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017594","name":"Medical Science and Technology Project of Zhejiang Province","doi-asserted-by":"publisher","award":["WKJ\u2010ZJ\u20102202"],"award-info":[{"award-number":["WKJ\u2010ZJ\u20102202"]}],"id":[{"id":"10.13039\/501100017594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Targeted protein degradation (TPD) represents a transformative therapeutic paradigm that harnesses the cellular degradation machinery to pharmacologically eliminate disease\u2010causing proteins with aberrant expression. This work here reports the first design of an HSP70 interactome\u2010mediated proteolysis targeting chimera (HSP70\u2010PROTAC) for the degradation of the intracellular therapeutically relevant proteins via dual processes of ubiquitin\u2010proteasomal degradation (UPS) and chaperone\u2010mediated autophagy (CMA). By hijacking the highly expressed heat shock cognate protein (Hsc70) isoform complex in tumor tissues to glutathione peroxidase 4 (GPX4) protein, this work successfully develops an HSP70\u2010PROTAC molecule GDAz\u20103 that potently and rapidly eliminates GPX4 in HT1080 cells, thereby triggering ferroptosis with high selectivity. Correspondingly, GDAz\u20103 exhibits a remarkable tumor\u2010inhibitory effect in the HT1080 xenograft tumor mouse model without obvious toxicity. In addition, this work demonstrates the versatility of HSP70\u2010based PROTACs by effectively degrading additional endogenous bromodomain\u2010containing protein 4 (BRD4) in cancer cells. More importantly, the degradation of GPX4 mediated by GDAz\u20103 occurs with comparable efficiency in CRBN\/VHL\u2010knockdown cells and 786\u2010O cells intrinsically lacking VHL expression, which facilitates expanding the application scope and overcoming drug resistance of traditional PROTAC. These findings suggest that HSP70\u2010PROTAC is a novel and feasible strategy for the future development of TPD technology.<\/jats:p>","DOI":"10.1002\/advs.202513655","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T02:12:11Z","timestamp":1765591931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["HSP70 Interactome\u2010Mediated Proteolysis Targeting Chimera (HSP70\u2010PROTAC) for Ferroptosis\u2010Driven Cancer Treatment"],"prefix":"10.1002","volume":"13","author":[{"given":"Jinyun","family":"Dong","sequence":"first","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liang","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zumei","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqun","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanning","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Institute for Biotechnology College of Pharmacy and Health Sciences St. John's University  Queens NY 11439 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maohua","family":"Cai","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangzhao","family":"Pan","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Miao","sequence":"additional","affiliation":[{"name":"MOE Frontier Science Centre for Precision Oncology University of Macau  Macau SAR 999078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe\u2010Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Institute for Biotechnology College of Pharmacy and Health Sciences St. John's University  Queens NY 11439 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfang","family":"Tao","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Blood\u2010Stasis\u2010Toxin Syndrome Zhejiang Chinese Medical University China Collaborative Graduate School of Traditional Chinese Medicine Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuelei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8559-616X","authenticated-orcid":false,"given":"Jiang\u2010Jiang","family":"Qin","sequence":"additional","affiliation":[{"name":"Center for Innovative Drug Research Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou Zhejiang 310022 China"},{"name":"Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang 310022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202300379"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201904197"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102999"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116387"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24297"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2024.07.038"},{"key":"e_1_2_10_8_1","first-page":"144","volume":"133","author":"Seibt T. M.","year":"2019","journal-title":"Biol. Med."},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2218764"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00569"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.2c00236"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00967"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117370"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.04.011"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202423524"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.038"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2022.08.003"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202206277"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117710"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106461"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115343"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.3c00571"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.115072"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2023.117352"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c08964"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1336-y"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-024-01601-1"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01518"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2010.10.014"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12751"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0805-736"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200802801"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116520"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.8840"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kve246"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1379\/1466-1268(2003)008<0303:CALBTC>2.0.CO;2"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1547"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c02681"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202409498"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99319"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.7.4613"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115824"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0375"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44237-4"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.2174\/18715206113139990093"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202508427"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202415626"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-971"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01648"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3SC02361C"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202513655","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202513655","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202513655","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T08:44:01Z","timestamp":1773305041000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202513655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/advs.202513655"],"URL":"https:\/\/doi.org\/10.1002\/advs.202513655","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]},"assertion":[{"value":"2025-07-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13655"}}