Chemotherapy was conventionally applied to kill
cancer cells, but regrettably, they also induce damage to normal cells with high-proliferative capacity resulting in
cardiotoxicity, nephrotoxicity, peripheral nerve toxicity, and ovarian toxicity. Of these,
chemotherapy-induced ovarian damages mainly include but are not limited to decreased ovarian reserve,
infertility, and ovarian
atrophy. Therefore, exploring the underlying mechanism of chemotherapeutic
drug-induced ovarian damage will pave the way to develop fertility-protective adjuvants for female patients during conventional
cancer treatment. Herein, we firstly confirmed the abnormal
gonadal hormone levels in patients who received
chemotherapy and further found that conventional chemotherapeutic drugs (
cyclophosphamide, CTX;
paclitaxel, Tax;
doxorubicin, Dox and
cisplatin, Cis) treatment significantly decreased both the ovarian volume of mice and the number of primordial and
antral follicles and accompanied with the ovarian
fibrosis and reduced ovarian reserve in animal models. Subsequently, Tax, Dox, and Cis treatment can induce the apoptosis of ovarian granulosa cells (GCs), likely resulting from excessive
reactive oxygen species (ROS) production-induced oxidative damage and impaired cellular anti-oxidative capacity. Thirdly, the following experiments demonstrated that Cis treatment could induce
mitochondrial dysfunction through overproducing
superoxide in GCs and trigger lipid peroxidation leading to ferroptosis, first reported in
chemotherapy-induced ovarian damage. In addition,
N-acetylcysteine (NAC) treatment could alleviate the Cis-induced toxicity in GCs by downregulating cellular ROS levels and enhancing the anti-oxidative capacity (promoting the expression of
glutathione peroxidase, GPX4; nuclear factor erythroid 2-related factor 2, Nrf2 and
heme oxygenase-1, HO-1). Our study confirmed the
chemotherapy-induced chaotic hormonal state and ovarian damage in preclinical and clinical examination and indicated that chemotherapeutic drugs initiated ferroptosis in ovarian cells through excessive ROS-induced lipid peroxidation and
mitochondrial dysfunction, leading to ovarian cell death. Consequently, developing fertility protectants from the
chemotherapy-induced oxidative stress and ferroptosis perspective will ameliorate ovarian damage and further improve the life quality of
cancer patients.