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This study demonstrates that human umbilical cord mesenchymal stem cell\u2013derived exosomes can partially improve ovarian aging-associated phenotypes by activating NRF2-mediated antioxidant defenses and inhibiting ferroptosis, offering a promising cell-free therapeutic strategy.<\/jats:p>\n                  <jats:p>Abstract: Ovarian aging is characterized by a decline in oocyte quantity and quality, often driven by oxidative stress and cellular damage. Human umbilical cord mesenchymal stem cell\u2013derived exosomes (hUC-MSC-Exos) have emerged as a potent cell-free therapy for regenerative medicine. In this study, female mice with early ovarian aging (31\u201333\u2009weeks; n\u2009=\u20098 per group) received 10 intraperitoneal injections of hUC-MSC-Exos (240\u2009\u00b5L\/dose, 6.5\u2009\u00d7\u200910\u00b9\u2070 particles\/mL) over 2\u2009weeks. Ovarian function, follicular development, DNA damage, and ferroptosis-related markers were evaluated. hUC-MSC-Exo treatment significantly increased the number of primary and antral follicles without a significant change in primordial follicle counts. Exosome administration reduced genomic stress, evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) intensity, and improved oocyte yield and mitochondrial metabolic state. Mechanistically, hUC-MSC-Exos promoted the nuclear translocation of Nuclear factor erythroid 2 related factor 2 (NRF2), a master antioxidant regulator. This activation was accompanied by the suppression of ferroptosis, indicated by upregulation of GPX4 and SLC7A11 and downregulation of 4-HNE and ACSL4. Furthermore, exosome treatment restored ovarian functional markers (anti-M\u00fcllerian hormone [AMH], BMP15) and steroidogenic proteins (CYP11A1, 3\u03b2-HSD, StAR). These findings suggest that hUC-MSC-Exos mitigate age-related ovarian dysfunction by modulating NRF2-mediated antioxidant defenses and inhibiting ferroptosis, offering a promising candidate that warrants validation with functional reproductive endpoints.<\/jats:p>","DOI":"10.1093\/reprod\/xaag104","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:39:55Z","timestamp":1787657995000},"source":"Crossref","is-referenced-by-count":0,"title":["Human umbilical cord mesenchymal stem cell\u2013derived exosomes ameliorate ovarian aging by inhibiting ferroptosis"],"prefix":"10.1093","volume":"172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3773-9015","authenticated-orcid":false,"given":"Chia-Jung","family":"Li","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital , Kaohsiung,","place":["Taiwan"]},{"name":"Institute of Biopharmaceutical Sciences, National Sun Yat-sen University , Kaohsiung,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Te","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital , Kaohsiung,","place":["Taiwan"]},{"name":"Center of General Education, Shu-Zen Junior College of Medicine and Management , Kaohsiung,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Hsuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital , Kaohsiung,","place":["Taiwan"]},{"name":"Center of General Education, Shu-Zen Junior College of Medicine and Management , Kaohsiung,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computing, National University of Singapore , Singapore,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4411-044X","authenticated-orcid":false,"given":"Zhi-Hong","family":"Wen","sequence":"additional","affiliation":[{"name":"National Museum of Marine Biology & Aquarium , Pingtung,","place":["Taiwan"]},{"name":"Department of Marine Biotechnology and Resources, National Sun Yat-sen University , Kaohsiung,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hao","family":"Tsui","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital , Kaohsiung,","place":["Taiwan"]},{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital , Taipei,","place":["Taiwan"]},{"name":"Department of Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"2026091720311526000_xaag104-B1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41392-024-02088-5","article-title":"In defence of ferroptosis","volume":"10","author":"Alves","year":"2025","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"2026091720311526000_xaag104-B2","doi-asserted-by":"publisher","first-page":"113914","DOI":"10.1016\/j.intimp.2024.113914","article-title":"ADSCs-derived exosomes suppress macrophage ferroptosis via the SIRT1\/NRF2 signaling axis to alleviate acute lung injury in sepsis","volume":"146","author":"Bai","year":"2025","journal-title":"International Immunopharmacology"},{"key":"2026091720311526000_xaag104-B3","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1210\/er.2009-0006","article-title":"Ovarian aging: Mechanisms and clinical consequences","volume":"30","author":"Broekmans","year":"2009","journal-title":"Endocrine Reviews"},{"key":"2026091720311526000_xaag104-B4","doi-asserted-by":"publisher","first-page":"642","DOI":"10.14245\/ns.2448038.019","article-title":"Inhibition of ferroptosis by mesenchymal stem cell-derived exosomes in acute spinal cord injury: Role of Nrf2\/GCH1\/BH4 axis","volume":"21","author":"Chen","year":"2024","journal-title":"Neurospine"},{"key":"2026091720311526000_xaag104-B5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/s1388-1981(00)00147-5","article-title":"Steroidogenic acute regulatory protein (StAR) and the intramitochondrial translocation of cholesterol","volume":"1529","author":"Christenson","year":"2000","journal-title":"Biochimica et Biophysica Acta"},{"key":"2026091720311526000_xaag104-B6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.omtn.2020.05.013","article-title":"Exosomal miRNA-320a is released from hAMSCs and regulates SIRT4 to prevent reactive oxygen species generation in POI","volume":"21","author":"Ding","year":"2020","journal-title":"Molecular Therapy. 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