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Ferroptosis represents a promising therapeutic approach for OVCA, which could effectively overcome tumor resistance. Nevertheless, the traditional ferroptosis inducers lack specificity and selectivity, resulting in poor therapeutic effects. Here, we identified a novel tRNA\u2010derived fragment, tRF\u201021\u2010XSXMSL73E (tRF\u201021), which could serve as a ferroptosis inducer to efficiently suppress OVCA growth through dual inhibition of the system Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/glutathione (GSH)\/peroxidase 4 (GPX4) axis without causing obvious side effects. Mechanistically, tRF\u201021 promotes SLC3A2 ubiquitination via SPOP E3 ligase and destabilizes SLC7A11 mRNA by disrupting NSUN2\u2010mediated m\n                    <jats:sup>5<\/jats:sup>\n                    C methylation. This dual\u2010inhibition effect on the system Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    \/GSH\/GPX4 axis leads to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death. To enhance therapeutic delivery, we engineered a pH\u2010responsive nanoplatform (tRF\u201021@EPH) with an ellagic acid core, polyetherimide (PEI) intermediate layer, and hyaluronic acid shell, enabling nuclease protection and tumor\u2010specific uptake. This system markedly improved tRF\u201021 efficacy with minimal toxicity, providing a novel RNA\u2010based strategy for OVCA treatment.\n                  <\/jats:p>","DOI":"10.1002\/adma.202521078","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T04:48:38Z","timestamp":1774932518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Tumor\u2010Targeted tRF Therapeutics Triggers Ovarian Cancer Ferroptosis via Dual Inhibition of System Xc\n                    <sup>\u2212<\/sup>"],"prefix":"10.1002","volume":"38","author":[{"given":"Jiang","family":"Ouyang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Department of Gynecologic Oncology Research Office Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of Maternal\u2010Fetal Medicine The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Guangzhou Institute of Cancer Research the Affiliated Cancer Hospital &amp; School of Biomedical Engineering Guangzhou Medical University  Guangzhou China"},{"name":"Center for Nanomedicine and Department of Anesthesiology Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jielin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Department of Gynecologic Oncology Research Office Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of Maternal\u2010Fetal Medicine The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Department of Gynecologic Oncology Research Office Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of Maternal\u2010Fetal Medicine The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Tao","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research the Affiliated Cancer Hospital &amp; School of Biomedical Engineering Guangzhou Medical University  Guangzhou China"},{"name":"Center for Nanomedicine and Department of Anesthesiology Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Institute of Cancer Research the Affiliated Cancer Hospital &amp; School of Biomedical Engineering Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bumin","family":"Xie","sequence":"additional","affiliation":[{"name":"Cancer Hospital of Dalian University of Technology Cancer Hospital of China Medical University Liaoning Cancer Hospital &amp; Institute  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Department of Gynecologic Oncology Research Office Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of Maternal\u2010Fetal Medicine The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Cancer Hospital of Dalian University of Technology Cancer Hospital of China Medical University Liaoning Cancer Hospital &amp; Institute  Shenyang Liaoning China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4277-3728","authenticated-orcid":false,"given":"Wei","family":"Tao","sequence":"additional","affiliation":[{"name":"Center for Nanomedicine and Department of 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