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To gain a deeper understanding of the influence of ferroptosis-related genes on ovarian aging, we employed a comprehensive approach encompassing spatial transcriptomics, single-cell RNA sequencing, human ovarian pathology, and clinical biopsy. This investigation revealed the intricate interactions between ferroptosis and cellular energy metabolism in aging germ cells, shedding light on the underlying mechanisms. Our study involved 75 patients with ovarian senescence insufficiency, and we utilized multi-histological predictions of ferroptosis-related genes. Following a two-month supplementation period with DHEA, Ubiquinol CoQ10, and Cleo-20 T3, we examined the changes in hub genes. Our results showed that TFRC, NCOA4, and SLC3A2 were significantly reduced and GPX4 was increased in the supplement group, confirming our prediction based on multi-omic analysis. Our hypothesis is that supplementation would enhance the mitochondrial tricarboxylic acid cycle (TCA) or electron transport chain (ETC), resulting in increased levels of the antioxidant enzyme GPX4, reduced lipid peroxide accumulation, and reduced ferroptosis. Overall, our results suggest that supplementation interventions have a notable positive impact on in vitro fertilization (IVF) outcomes in aging cells by improving metal ion and energy metabolism, thereby enhancing oocyte quality in older women.<\/jats:p>","DOI":"10.3390\/nu15112461","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T02:00:19Z","timestamp":1685066419000},"page":"2461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Investigating the Role of Ferroptosis-Related Genes in Ovarian Aging and the Potential for Nutritional Intervention"],"prefix":"10.3390","volume":"15","author":[{"given":"Pei-Hsuan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Ping","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3773-9015","authenticated-orcid":false,"given":"Chia-Jung","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5063-6793","authenticated-orcid":false,"given":"Li-Te","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Sheu","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"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":"Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiin-Tsuey","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8090-8657","authenticated-orcid":false,"given":"Kuan-Hao","family":"Tsui","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan"},{"name":"Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Obstetrics and Gynaecology, National Yang-Ming University School of Medicine, Taipei 112, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"934","DOI":"10.14336\/AD.2020.1113","article-title":"The Molecular Regulation in the Pathophysiology in Ovarian Aging","volume":"12","author":"Li","year":"2021","journal-title":"Aging Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.tcb.2015.10.014","article-title":"Ferroptosis: Death by Lipid Peroxidation","volume":"26","author":"Yang","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/bs.ircmb.2018.05.006","article-title":"Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases","volume":"340","author":"Giorgi","year":"2018","journal-title":"Int. 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