The interaction between endoplasmic reticulum stress and ferroptosis in ovarian diseases

Ovarian diseases including polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and ovarian cancer, critically impact women’s reproductive health. Growing evidence implicates endoplasmic reticulum (ER) stress and ferroptosis as key collaborative pathways in their pathogenesis. This review aims to systematically clarify the molecular mechanisms of ER stress and ferroptosis, deeply explore the crosstalk between them, and evaluate their specific roles in the occurrence, development and treatment of major ovarian diseases. We conducted a systematic review (up to July 2025) using PubMed and Web of Science, focusing on studies linking these pathways to ovarian pathophysiology. ER stress restores intracellular homeostasis by activating the unfolded protein response (UPR), but sustained or severe stress ultimately leads to cell death. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Studies have found that common regulatory factors such as activating transcription factor 4 (ATF4), glutathione metabolism key enzyme ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) and nuclear factor erythroid 2-related factor 2 (Nrf2) constitute the key molecular bridges for the interaction between the two. These mechanisms collectively regulate core pathophysiological processes such as follicular atresia, ovarian dysfunction and malignant progression of tumors. The interaction network between ER stress and ferroptosis plays a central role in the pathophysiological process of ovarian diseases. Targeting this interactive axis is expected to provide new strategies for the protection of ovarian dysfunction and the therapeutic intervention of gynecological tumors. More in vivo studies and clinical transformation explorations are needed in the future to verify these findings and promote their clinical application.