Exploring the molecular mechanisms and potential therapeutic strategies of ferroptosis in ovarian cancer

Abstract

The morbidity rate of ovarian cancer, a malignant tumour in gynaecological tumours, is rising, and it is considered to be the most lethal cancer. The majority of patients are typically diagnosed during the advanced stages of the illness due to the elusive characteristics of ovarian cancer and an absence of highly sensitive and specific diagnostic indicators. Surgical excision of the lesions, along with chemotherapy, is the conventional treatment for ovarian cancer; however, resistance to platinum-based chemotherapeutic drugs and molecular targeted therapies frequently arises. Improving the survival rate and prognosis of patients with end-stage or recurring ovarian cancer requires the identification of new therapeutic targets due to the absence of efficient medications, and this has emerged as a highly demanding issue. Studies have demonstrated that ferroptosis effectively hinders the proliferation of ovarian cancer and induces the demise of malignant cells. Ferroptosis is composed of the cystine/glutamate antiporter system (the system Xc-) and glutathione peroxidase 4 (GPX4). Solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) play crucial roles in the regulation of ferroptosis by facilitating the uptake of cystine into cells and the efflux of glutamate out of cells, respectively. In cells, GPX4 is the exclusive enzyme employed for reducing liposomal peroxide through glutathione peroxidase activity. The occurrence of ferroptosis in ovarian cancer is strongly associated with three main pathways, namely, the GPX4-glutathione (GSH) protective pathway, the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) protective pathway, and the guanosine 5'-triphosphate cyclohydrolase I (GCH1) protective pathway. In ovarian cancer cells, the postsynaptic density-95, discs-large, zona occludens 1 (PDZ)-binding motif-angiopoietin-like 4-nicotinamide adenine dinucleotide phosphate oxidases 2 (TAZ-ANGPTL4-NOX2) pathway can be regulated by Yes-associated protein (YAP)/TAZ, a downstream component of the Hippo pathway, leading to the modulation of ferroptosis. By targeting microRNA-587, lncRNA ADAMTS9 antisense RNA 1 (ADAMTS9-AS1) can modulate the expression of SLC7A11 and reduce the occurrence of ferroptosis. Although ferroptosis holds promise in overcoming the resistance mechanism, there remain obstacles in utilizing it as a cancer treatment, including the potential harm of drugs to healthy cells. Hence, additional investigations are required to formulate safer and more efficient chemotherapy protocols for the treatment of ovarian cancer and other malignancies.