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The study identifies an extracellular sphingomyelin salvaging program that enables extracellular vesicle–mediated intracellular clearance of damaged mitochondria, acting as a mechanism complementary to mitophagy. Therapeutic targeting through repurposed eliglustat shows potent anti-cancer effects in vitro and in vivo, inducing ceramide-mediated compensatory mitophagy and promoting cancer cell death while attenuating tumor growth and extending survival in mouse models and xenografts.",{"@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/vesicle-mediated-mitochondrial-clearance-presents-an-actionable-metabolic-vulnerability-in-triple-negative-breast-cancer-article-abstract/433967/",{"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/vesicle-mediated-mitochondrial-clearance-presents-an-actionable-metabolic-vulnerability-in-triple-negative-breast-cancer-article-abstract/433967.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What mitochondrial quality control mechanism does the study highlight in TNBC?","Question",{"text":112,"@type":113},"It highlights extracellular sphingomyelin salvaging coupled with extracellular vesicle–mediated intracellular clearance of mitochondrial damage, complementary to mitophagy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does eliglustat affect the onco-metabolic pathway described?",{"text":117,"@type":113},"Repurposed eliglustat targets UGCG, producing ceramide-mediated compensatory mitophagy and promoting cancer cell death, with anti-tumor effects in vitro and in vivo.",{"name":119,"@type":110,"acceptedAnswer":120},"Which cancer contexts are used to assess therapeutic efficacy?",{"text":121,"@type":113},"Efficacy is tested in orthotopic syngeneic mouse models of TNBC and in human cell line-derived xenograft models, alongside cell-based in vitro experiments.","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},433967,1790922484,{"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":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Article  \nVesicle-mediated mitochondrial clearance presentsan actionable metabolic vulnerability in triplenegative breast cancer  \nAuthors  \nJody Vykoukal, Yihui Chen, Mingxin Zuo, ..., Banu Arun,  \nSamir Hanash, Johannes F. Fahrmann  \nCorrespondence  \n[jffahrmann@mdanderson.org](jffahrmann@mdanderson.org)  \nIn brief  \nVykoukal et al. describe an oncometabolic program of heightened sphingomyelin salvaging that supports extracellular vesicle-mediated mitochondrial quality control and is complementary to mitophagy. This program is characterized in triplenegative breast cancer. Therapeutic targeting via repurposing of eliglustat is demonstrated to elicit potent anti-cancer effects in vitro and in vivo.  \n• TNBC cells salvage extracellular sphingomyelin to support glycosphingolipid biosynthesis  \n• Enhanced sphingomyelin salvaging supports EV-mediated clearance of damaged mitochondria  \n• Targeting of UGCG via eliglustat exerts anti-cancer effects in vitro and in vivo  \nVykoukal et al., 2025, Cell Reports Medicine 6, 102478  \nDecember 16, 2025 © 2025 The Author(s) . Published by Elsevier Inc.  \n[https://doi.org/10.1016/j.xcrm.2025.102478](https://doi.org/10.1016/j.xcrm.2025.102478)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nVesicle-mediated mitochondrial clearance presentsan actionable metabolic vulnerability  \nin triple-negative breast cancer  \nJody Vykoukal,1,5 Yihui Chen,1,5 Mingxin Zuo,1 Riccardo Ballar`o,1 Monica J. Hong,1 Hansini Krishna,1  \nDaniela B. Rodriquez-Perera,1 Hiroyuki Katayama,1 Ehsan Irajizad,1 Ranran Wu,1 Ricardo A. Le´on-Letelier,1  \nJennifer B. Dennison,1 Angelica M. Gutierrez,4 Adriana Paulucci-Holthauzen,2 Timothy C. Thompson,3 Leona Rusling,1 Yining Cai,1 Fu Chung Hsiao,1 Soyoung Park,1 Banu Arun,4 Samir Hanash,1 and Johannes F. Fahrmann1,6,*  \n1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  \n2Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  \n3Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  \n4Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  \n5These authors contributed equally  \n6Lead contact  \n*Correspondence: [jffahrmann@mdanderson.org](jffahrmann@mdanderson.org)  \n[https://doi.org/10.1016/j.xcrm.2025.102478](https://doi.org/10.1016/j.xcrm.2025.102478)  \nSUMMARY  \nSelective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC) . Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control inTNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death in vitro and attenuates tumor growth and prolongs overall survival at clinically achievable doses in orthotopic syngeneic mouse models of TNBC as well as in human cell line-derived xenograft models. Our study defines an unexplored mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.  \nINTRODUCTION  \nMitochondria are semi-autonomous intracellular organelles that are highly dynamic and responsive to metabolic and extracellular insults.1 Mitochondria play central roles in cancer development and progression by contributing to cell proliferation, apoptosis, calcium ion storage, energetics, and production of reactive oxygen species (ROS) .1 Mitochondrial dynamics in cancer cells is regulated t","cbCaiibzxRC8GN4p","https://ap.wps.com/l/cbCaiibzxRC8GN4p","pdf",16725578,27,"English","# SUMMARY\n# INTRODUCTION","[{\"question\":\"What mitochondrial quality control mechanism does the study highlight in TNBC?\",\"answer\":\"It highlights extracellular sphingomyelin salvaging coupled with extracellular vesicle–mediated intracellular clearance of mitochondrial damage, complementary to mitophagy.\"},{\"question\":\"How does eliglustat affect the onco-metabolic pathway described?\",\"answer\":\"Repurposed eliglustat targets UGCG, producing ceramide-mediated compensatory mitophagy and promoting cancer cell death, with anti-tumor effects in vitro and in vivo.\"},{\"question\":\"Which cancer contexts are used to assess therapeutic efficacy?\",\"answer\":\"Efficacy is tested in orthotopic syngeneic mouse models of TNBC and in human cell line-derived xenograft models, alongside cell-based in vitro experiments.\"}]","Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer - Article abstract | PDF",1790666427,68]