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Ferroptosis is a programmed cell death characterized by lipid peroxide accumulation, distinct from apoptosis induced by DNA or mitotic damage. This study evaluates ferroptosis sensitivity across cell lines, tracking ACSL4 extracellular export via exosomes and identifying upstream regulators using IP-MS and validation assays. VIPAS39 is found to drive ACSL4 sorting into late endosomes and exosomal release, enabling ferroptosis evasion and tumor growth suppression when targeted.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/vipas39-confers-ferroptosis-resistance-in-epithelial-ovarian-cancer-through-exporting-acsl4/373143/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/vipas39-confers-ferroptosis-resistance-in-epithelial-ovarian-cancer-through-exporting-acsl4/373143.png","ImageObject",300,407,{"name":92,"@type":93},"Genevieve","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does ferroptosis play in epithelial ovarian cancer treatment?","Question",{"text":112,"@type":113},"Ferroptosis is a regulated, lipid-peroxidation-driven form of programmed cell death considered as an alternative anti-cancer approach for epithelial ovarian cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do the authors evaluate ferroptosis sensitivity and ACSL4 export?",{"text":117,"@type":113},"They assess cell viability and lipid peroxidation, and use live-cell imaging with a CD63-pHuji reporter to monitor extracellular export of ACSL4 via exosomes.",{"name":119,"@type":110,"acceptedAnswer":120},"Why are some epithelial ovarian cancer cells resistant to ferroptosis?",{"text":121,"@type":113},"Resistant cells show unusually low ACSL4 levels because ACSL4 is exported out of the cells through exosomes, preventing ferroptosis execution.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},373143,1790269312,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},1374391974585,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Articles   \nVIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4  \nYuening Jiang,a,b,c,d Jie Li,a,b,c,d Tianzhen Wang,a,b,c,d Xiaoyang Gu,a,b,c,d Xinyu Li,f,g Zhaofei Liu,h Wei Yue,i,∗∗ and Mo Lia,b,c,d,e, ∗  \naState Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China  \nbNational Clinical Research Centre for Obstetrics and Gynaecology, Third Hospital, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China  \ncKey Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, 100191, China  \ndBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology (Peking University Third Hospital), Beijing, 100191, China  \neDepartment of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China  \nfDepartment of Animal Science, College of Animal Science, Hebei North University, Zhangjiakou, Hebei Province, China gDepartment of Gynecology and Obstetrics, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China  \nhDepartment of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China iInterdisciplinary Eye Research Institute (EYE-X Institute) Bengbu Medical University, Bengbu, Anhui, 233030, China  \nSummary  \nBackground The high mortality rate associated with epithelial ovarian cancer (EOC) is primarily due to recurrence and chemoresistance, underscoring the urgent need for innovative therapeutic approaches that leverage newly identified vulnerabilities in cancer cells. While conventional chemotherapies induce apoptosis by targeting DNA or mitotic machinery, ferroptosis represents a new distinct form of programmed cell death characterised by the accumulation of lipid peroxides.  \nMethods The sensitivity of different EOC cell lines to ferroptosis inducers was evaluated using cell viability assays and lipid peroxidation measurements. Live-cell imaging with the pH-sensitive CD63-pHuji reporter was performed to track the extracellular export of acyl-CoA synthetase long-chain family member 4 (ACSL4) via exosomes. The upstream regulator of ACSL4 were identified through immunoprecipitation-mass spectrometry (IP-MS) and validated using protein binding assays. Finally, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were utilised to evaluate the therapeutic potential overcoming ferroptosis resistance.  \nFindings In this study, we found that interferon (IFN)-γ combined with arachidonic acid (AA), which are endogenous ferroptosis inducers, could initiate ferroptosis in most EOC cells. However, some EOC cells displayed significant resistance. Contrary to the typical increase in ACSL4 protein observed in ferroptosis-sensitive cells, resistant EOC cells exhibited surprisingly low levels of this pro-ferroptotic lipid metabolic protein. Intriguingly, this reduction is attributed to the exosomal expulsion of ACSL4 protein, revealing a distinct cellular mechanism to evade ferroptosis. We further identified VIPAS39 as a pivotal regulator in sorting ACSL4 into late endosomes, thereby facilitating their subsequent release as exosomes. Notably, targeting VIPAS39 not only overcomes the resistance to ferroptotic cell death but also markedly suppresses tumour growth.  \nInterpretation Our findings uncover the crucial role of VIPAS39 in ferroptosis evasion by facilitating the exporting of ACSL4 protein via exosomes, highlighting VIPAS39 as a promising target for ferroptosis-based anti-cancer therapy.  \nFunding Funded by Beijing Municipal Natural Science Foundation (Key program Z220011), National Nat","cbCaie5GdaZQ0XVs","https://ap.wps.com/l/cbCaie5GdaZQ0XVs","pdf",5533178,"English","# Summary\n## Background\n## Methods\n## Findings\n## Interpretation\n# Research in context\n## Evidence before this study\n## Added value of this study","[{\"question\":\"What role does ferroptosis play in epithelial ovarian cancer treatment?\",\"answer\":\"Ferroptosis is a regulated, lipid-peroxidation-driven form of programmed cell death considered as an alternative anti-cancer approach for epithelial ovarian cancer.\"},{\"question\":\"How do the authors evaluate ferroptosis sensitivity and ACSL4 export?\",\"answer\":\"They assess cell viability and lipid peroxidation, and use live-cell imaging with a CD63-pHuji reporter to monitor extracellular export of ACSL4 via exosomes.\"},{\"question\":\"Why are some epithelial ovarian cancer cells resistant to ferroptosis?\",\"answer\":\"Resistant cells show unusually low ACSL4 levels because ACSL4 is exported out of the cells through exosomes, preventing ferroptosis execution.\"}]","VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4 | PDF",1790197106]