Selenium nanoparticles mitigate Cyclophosphamide-Induced premature ovarian failures in mice by activating PI3K/AKT signaling pathway and inhibiting ferroptosis

The therapeutic role and mechanisms of selenium nanoparticles (SeNPs) in cyclophosphamide (CTX)-induced premature ovarian failure (POF) remain unclear. In the present study, female mice were treated with CTX to induce POF, followed by SeNPs administration for 14 consecutive days. Ovarian weight, index, and serum hormone levels were measured to assess ovarian function. Histological examination of ovarian tissues was conducted to examine morphological changes, folliculogenesis, DNA damage, and apoptosis. Transcriptomic analysis was performed to identify the underlying molecular mechanisms, with in vitro studies on ovarian granulosa cells employed to validate the findings. The results confirmed that SeNPs administration effectively restored ovarian morphology and function, increasing the number of developing follicles and decreasing the number of atretic follicles. Notably, SeNPs significantly reversed CTX-induced hormonal disturbances: estradiol (E₂) levels increased from 186.24 ± 14.72 pM (CTX group) to 258.28 ± 7.53 pM (SeNPs group); follicle-stimulating hormone (FSH) decreased from 20.74 ± 1.13 IU/L to 15.96 ± 1.07 IU/L; luteinizing hormone (LH) declined from 24.88 ± 1.16 ng/mL to 18.04 ± 1.60 ng/mL; and anti-Müllerian hormone (AMH) rose from 164.02 ± 8.57 pg/mL to 230.30 ± 12.01 pg/mL. Moreover, SeNPs attenuated CTX-induced DNA damage and apoptosis of granulosa cells. Transcriptomic analysis identified that SeNPs exert their protective effects against CTX-induced POF by activating the PI3K/AKT signaling pathway and inhibiting ferroptosis, as evidenced by the expression patterns of PI3K/AKT signaling pathway-related proteins and ferroptosis-related markers in granulosa cells. In conclusion, SeNPs effectively protect against CTX-induced POF by enhancing ovarian function, promoting folliculogenesis, and inhibiting DNA damage and apoptosis of granulosa cells. These protective effects are mediated through the activation of the PI3K/AKT signaling pathway and suppression of ferroptosis. Our findings suggest that SeNPs hold promise as a promising therapeutic strategy for ovarian dysfunction, particularly in the context of chemotherapy-induced POF.