Advances in ferroptosis research in ovarian cancer: molecular mechanisms and therapeutic perspectives.

Ovarian cancer is one of the most aggressive malignancies in the female genital system and presents a poor prognosis. Its high rate of recurrence and emergence of acquired resistance to the current chemotherapeutic approaches significantly restrict its long-term therapeutic efficacy. While treatment strategies including cytoreductive surgery (CRS) plus platinum (Pt)-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have brought clinical benefits to a proportion of patients, the majority eventually suffer cancer relapse post-treatment. This finding suggests that classical forms of cell death may not fully explain treatment outcomes, survival, and resistance in ovarian cancer. Ferroptosis is a nonapoptotic mode of cell death that results from the iron-dependent and lethal peroxidation of lipids. Its onset and progression are contextually regulated by iron homeostasis, lipid metabolism, and redox balance, and also tightly involved in the tumor metabolic reprogramming and adaptation to the tumor microenvironment (TME). Under therapeutic pressure, ovarian cancer cells may become more susceptible to ferroptosis while simultaneously suppressing ferroptotic cell death through multilayered regulatory systems, including glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter system (system Xc-) antioxidant defenses, acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation (LPO), and nuclear receptor coactivator 4 (NCOA4)-dependent ferritinophagy, in order to survive. This biphasic behaviour is strongly linked to treatment resistance and disease recurrence. In this review, the molecular mechanisms by which ferroptosis operates in ovarian cancer are systematically reviewed, and a profile of regulatory factors - genetic, epigenetic, metabolic, and microenvironmental - is presented. Special attention is given to a summary of current literature on the cross-talk between ferroptosis and the sensitivity of Pt-based chemotherapy and PARP inhibitors, cancer stem cell properties within ovarian cancer, as well as the TME. In addition, the current progress in ferroptosis-inducing strategies, nanodelivery systems, and related biomarkers for precision therapy and therapeutic response prediction is comprehensively discussed.