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S14G-Humanin (HNG), a potent analogue of Humanin, exhibits strong antioxidant and anti-apoptotic properties and has demonstrated cytoprotective effects in various tissues, including the ovary. In this study, a cyclophosphamide (CP)-induced POI mouse model was established to evaluate both the ovarian damage induced by chemotherapy and the protective effects of HNG. HNG administration significantly increased the number of primordial follicles (P\u2009=\u20090.044) and growing follicles (all P\u2009&amp;gt;\u20090.05), as well as corpora lutea (P\u2009=\u20090.09). Moreover, HNG markedly improved oocyte quality (P\u2009=\u20090.009), significantly lowering the proportion of abnormal ovulated oocytes (P\u2009=\u20090.002). Fertility outcomes were also enhanced: CP treatment significantly reduced litter size compared to controls (4.6\u2009\u00b1\u20091.1 vs 8.0\u2009\u00b1\u20091.0; P\u2009&amp;lt;\u20090.001), whereas HNG treatment significantly mitigated this reduction (6.2\u2009\u00b1\u20090.8 vs 4.6\u2009\u00b1\u20091.1; P\u2009=\u20090.029). Mechanistically, HNG alleviated oxidative stress and apoptosis in ovarian tissues (all P\u2009&amp;lt;\u20090.05), reduced ROS levels (P\u2009=\u20090.034), and restored mitochondrial membrane potential (P\u2009=\u20090.004) in a human granulosa cell line. Furthermore, HNG significantly upregulated PGC-1\u03b1 expression and enhanced AMPK phosphorylation in both in vivo and in vitro models (both P\u2009&amp;lt;\u20090.05). Collectively, these findings demonstrate that HNG confers significant protection against chemotherapy-induced ovarian damage and highlight its potential as a novel therapeutic agent for chemotherapy-induced ovarian damage.<\/jats:p>","DOI":"10.1093\/molehr\/gaaf042","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T11:50:55Z","timestamp":1755085855000},"source":"Crossref","is-referenced-by-count":2,"title":["S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model"],"prefix":"10.1093","volume":"31","author":[{"given":"Jin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Wuhan Third Hospital (Tongren Hospital of Wuhan University) , Wuhan,","place":["China"]},{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University , Kunming,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Zou","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan,","place":["China"]},{"name":"Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital Affiliated to Nanchang Medical College , Nanchang,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University , Kunming,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6918-095X","authenticated-orcid":false,"given":"Changhong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology , Wuhan,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4787-4074","authenticated-orcid":false,"given":"Meng","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University , 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