S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model.

Premature ovarian insufficiency (POI) is a major cause of female infertility, for which effective therapies remain limited. 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-induced POI (CP-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 numbers of primordial follicles (P = 0.044) and growing follicles (all P > 0.05), as well as corpora luteum (P = 0.09). Moreover, HNG markedly improved oocyte quality (P = 0.009), significantly lowering the proportion of abnormal ovulated oocytes (P = 0.002). Fertility outcomes were also enhanced: CP treatment significantly reduced litter size compared to controls (4.6 ± 1.1 vs. 8.0 ± 1.0; P < 0.001), whereas HNG treatment significantly mitigated this reduction (6.2 ± 0.8 vs. 4.6 ± 1.1; P = 0.029). Mechanistically, HNG alleviated oxidative stress and apoptosis in ovarian tissues (all P < 0.05), reduced ROS levels (P = 0.034), and restored mitochondrial membrane potential (P = 0.004) in a human granulosa cell line. Furthermore, HNG significantly upregulated PGC-1α expression and enhanced AMPK phosphorylation in both in vivo and in vitro models (both P < 0.05). 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.