In rats, a modified version of the natural peptide humanin (called HNG) helped protect ovaries from damage caused by the chemotherapy drug cyclophosphamide. It kept hormone levels normal, saved egg‑containing follicles, and lowered cell death by cutting oxidative stress. Similar protective effects were seen in ovarian cells grown in the lab.

Can Gly[14]-humanin (HNG) improve cyclophosphamide-induced premature ovarian insufficiency (POI)? A POI model was induced in female rats by intraperitoneal injection of cyclophosphamide, followed by treatment with an intraperitoneal injection of HNG. Ovarian weight, ovarian index, regularity of the oestrous cycle, numbers of various types of follicle, hormone concentrations, and expression of the proliferation marker Ki67 were assessed in rats, and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was performed. The human ovarian granulosa cell line COV434 was exposed to the cyclophosphamide metabolite 4-hydroperoxy cyclophosphamide (4-HC), followed by HNG treatment. Cell viability and single-cell clone formation after HNG treatment were also evaluated. Reactive oxygen species (ROS), mitochondrial ROS (mtROS), 5-ethynyl-2'-deoxyuridine (EdU) and Ki67 expression, and Western blot analysis were performed to evaluate the expression of apoptosis-related proteins (Bcl-2 and Bax) and phosphorylated STAT3 protein. HNG mitigated cyclophosphamide-induced ovarian damage significantly in rats by restoring the disrupted oestrous cycle and sex hormone concentrations while reducing follicular depletion (P < 0.05) and apoptosis (P < 0.001). HNG treatment enhanced cell viability (P < 0.01) without causing abnormal cell proliferation. Furthermore, HNG ameliorated the 4-HC-induced damage in COV434 cells by enhancing cell viability, increasing the expression of proliferation markers (EdU and Ki67) and reducing ROS and mtROS concentrations (P < 0.05). HNG also decreased the 4-HC-induced elevation in Bax expression, and increased the expression of Bcl-2 and phosphorylated STAT3 (P < 0.05). The mitochondrial-derived peptide analogue HNG confers protection against cyclophosphamide-induced POI in rats by reducing oxidative stress and apoptosis. These findings suggest the potential of HNG as a therapeutic agent for preventing cyclophosphamide-induced POI in women.