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Gain- and loss-of-function analyses show that silencing PSMD14 suppresses TNBC growth, invasion, and metastasis, whereas PSMD14 overexpression has opposing effects. Mechanistically, PSMD14 reduces K63-linked ubiquitination of SF3B4, de-ubiquitinates it, and stabilizes SF3B4, enhancing FADS1 mRNA exon inclusion through HNRNPC-recognized m6A and activating Akt/mTOR signaling. Exogenous arachidonic acid plus PSMD14 knockdown triggers synthetic lethality, validated in TNBC organoids and patient-derived xenografts. Overall, PSMD14 supports TNBC progression and suggests biomarker and ferroptosis-mediated therapeutic strategies.",{"@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/targeting-psmd14-combined-with-arachidonic-acid-induces-synthetic-lethality-via-fads1-m6a-modification-in-triple-negative-breast-cancer/373314/",{"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/targeting-psmd14-combined-with-arachidonic-acid-induces-synthetic-lethality-via-fads1-m6a-modification-in-triple-negative-breast-cancer/373314.png","ImageObject",300,407,{"name":92,"@type":93},"WPS_1786070896","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does PSMD14 affect TNBC cell behavior in the study?","Question",{"text":112,"@type":113},"Silencing PSMD14 attenuates TNBC growth, invasion, and metastasis in vitro and in vivo, while PSMD14 overexpression produces the opposite effects.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What molecular pathway links PSMD14 to FADS1 and Akt/mTOR signaling?",{"text":117,"@type":113},"PSMD14 decreases K63-linked ubiquitination on SF3B4, stabilizing SF3B4; the SF3B4/HNRNPC complex then binds FADS1 mRNA, promotes exon inclusion via an m6A site, up-regulates FADS1, and activates Akt/mTOR signaling.",{"name":119,"@type":110,"acceptedAnswer":120},"How does arachidonic acid supplementation contribute to the therapeutic effect?",{"text":121,"@type":113},"Exogenous arachidonic acid combined with PSMD14 knockdown induces synthetic lethality, confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models.","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},373314,1790788854,{"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":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"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":144},549768072016,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","CANCER  \nTargeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer  \nYuanhang Yu1,2†, Jin Hu3†, Wenwen Wang4†, Hao Lei5, Zihan Xi1, Peiyi Zhang2, Ende Zhao6, Chong Lu1*, Hengyu Chen5*, Chunping Liu1*, Lei Li1*  \nDysregulation of deubiquitination is essential for cancer growth. However, the role of 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain-and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis ofTNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m6A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed inTNBC organoid (PDO) and TNBC patientderived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy forTNBC.  \ncopyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S.  \nGovernment Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) .  \nINTRODUCTION  \nBreast cancer has the highest incidence rate of any malignancy in women and is the second leading cause of cancer-related death in the world (1). Published reports showed that the estimated new cases of breast cancer were 287,850 (31%) and its estimated deaths account for 15% of new cases of breast cancer in 2022 (1) . Triple-negative breast cancer (TNBC) has the worst prognosis and overall survival (OS) among all the subtypes of breast cancer (2). Hence, further elucidating the potential molecular mechanisms associated with TNBC progression is of great significance.  \nDeubiquitination is considered to play key roles in maintaining cellular homeostasis and proper functions (3). Deubiquitinating enzyme (DUB) 26S proteasome non–adenosine triphosphatase regulatory subunit 14 (PSMD14), also known as RPN11 and POH1, isone of essential components of 19S proteasomal subunit (4). Through regulating protein deubiquitination and stabilization, PSMD14 is implicated in various biological processes, including differentiation (5), cell viability (6), pluripotency (7), autophagy (8), DNA break responses (9), and tumor progression (10) . Recently, overexpression of PSMD14 was reported in several kinds of human cancers, such as hepatocellular carcinoma (HCC), multiple myeloma, esophageal  \n1department of Breast and thyroid Surgery, Union hospital, tongji Medical college, huazhong University of Science and technology, Wuhan 430022, china. 2cancer center, Union hospital, tongji Medical college, huazhong University of Science and technology, Wuhan, hubei 430022, china. 3department of Breast and thyroid Surgery, Renmin hospital of Wuhan University, Wuhan 430060, china. 4department of Gynecology and Obstetrics, Union hospital, tongji Medical college, huazhong University of Science and technology, Wuhan 430022, china. 5department of Breast and thyroid Surgery, the Second Affiliated hospital of hainan Medical University and Key laboratory of tropical translational Medicine of Ministry of education and School of tropical Medicine, hainan Medical University, haikou 570311, china. 6department of Gastrointestinal Surgery, Union hospital, tongji Medical college, huazhong University of Science and technology, Wuhan 430022, china.  \n*[corresponding auth","cbCaieN7Zj8ACfSq","https://ap.wps.com/l/cbCaieN7Zj8ACfSq","pdf",17929476,"English","# Introduction\n## Breast cancer burden and TNBC prognosis\n## PSMD14 and deubiquitination in tumor progression\n## m6A RNA modification and HNRNPC\n## Ferroptosis and lipid peroxidation","[{\"question\":\"How does PSMD14 affect TNBC cell behavior in the study?\",\"answer\":\"Silencing PSMD14 attenuates TNBC growth, invasion, and metastasis in vitro and in vivo, while PSMD14 overexpression produces the opposite effects.\"},{\"question\":\"What molecular pathway links PSMD14 to FADS1 and Akt/mTOR signaling?\",\"answer\":\"PSMD14 decreases K63-linked ubiquitination on SF3B4, stabilizing SF3B4; the SF3B4/HNRNPC complex then binds FADS1 mRNA, promotes exon inclusion via an m6A site, up-regulates FADS1, and activates Akt/mTOR signaling.\"},{\"question\":\"How does arachidonic acid supplementation contribute to the therapeutic effect?\",\"answer\":\"Exogenous arachidonic acid combined with PSMD14 knockdown induces synthetic lethality, confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models.\"}]","Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m6A modification in triple-negative breast cancer | PDF",1790198866,48]