Chemotherapy impairs ovarian function through excessive ROS-induced ferroptosis

Area of Science:

• Reproductive Biology
• Toxicology
• Oncology

Background:

• Chemotherapy, while vital for cancer treatment, causes significant side effects including ovarian toxicity.
• Chemotherapy-induced ovarian damage manifests as decreased ovarian reserve, infertility, and atrophy, impacting female cancer patients' quality of life.

Purpose of the Study:

• To elucidate the mechanisms underlying chemotherapy-induced ovarian damage.
• To identify potential targets for fertility-protective adjuvants in female cancer patients undergoing chemotherapy.

Main Methods:

• Confirmed abnormal gonadal hormone levels in chemotherapy patients.
• Administered conventional chemotherapeutic drugs (CTX, Tax, Dox, Cis) to mouse models to assess ovarian volume, follicle count, fibrosis, and reserve.
• Investigated apoptosis, reactive oxygen species (ROS) production, mitochondrial dysfunction, and ferroptosis in ovarian granulosa cells (GCs).
• Evaluated the protective effects of N-acetylcysteine (NAC) against cisplatin-induced toxicity.

Main Results:

• Chemotherapy drugs significantly reduced ovarian volume, follicle count, and ovarian reserve, inducing fibrosis in mice.
• Tax, Dox, and Cis induced apoptosis in GCs, linked to excessive ROS production and impaired antioxidant capacity.
• Cisplatin triggered mitochondrial dysfunction and ferroptosis in GCs via ROS-mediated lipid peroxidation, a novel finding in chemotherapy-induced ovarian damage.
• NAC treatment mitigated cisplatin-induced GC toxicity by reducing ROS and enhancing antioxidant capacity (GPX4, Nrf2, HO-1 expression).

Conclusions:

• Chemotherapy induces a chaotic hormonal state and ovarian damage, confirmed in preclinical and clinical settings.
• Chemotherapeutic drugs initiate ovarian cell death through ferroptosis, driven by excessive ROS, lipid peroxidation, and mitochondrial dysfunction.
• Developing fertility protectants that target chemotherapy-induced oxidative stress and ferroptosis is essential for preserving ovarian function and improving cancer patients' quality of life.