Polyunsaturated fatty acids (PUFA) in ovarian cancer

Ovarian cancer remains the most lethal gynecological malignancy, with a majority of patients diagnosed at advanced stages, leading to high recurrence rates and platinum resistance. Traditional treatments like debulking and platinum-taxane chemotherapy, despite recent advancements with targeted therapies, still yield a poor prognosis. This has necessitated a shift in focus toward the unique metabolism of ovarian cancer cells, including the cancer stem cell population, which exhibit significant plasticity in energy generation by relying on both glycolysis and oxidative phosphorylation. This metabolic reprogramming underscores the critical role of fatty acid metabolism in supplying acetyl-CoA for the tricarboxylic acid cycle under conditions of stress and nutrient deprivation. Polyunsaturated fatty acids, including the omega-3 and omega-6 series, have emerged as crucial molecules in the etiology and therapeutic targeting of ovarian cancer. Omega-3 fatty acids consistently show anti-cancer properties by modulating cell signaling, inducing apoptosis via mitochondrial pathways, and potentially enhancing chemotherapeutic efficacy. The omega-6 family, traditionally viewed as pro-inflammatory and pro-cancer due to arachidonic acid and its metabolites, has revealed a complex, concentration-dependent role. Upstream omega-6 polyunsaturated fatty acids, specifically gamma-linolenic acid and dihomo-gamma-linolenic acid, demonstrate potent, selective cytotoxicity in cancer cells when the delta-5 desaturase pathway is compromised, inducing oxidative stress and apoptosis via unique free radical derivatives. Omega-6 metabolism may also interact dynamically with hormonal pathways, such as those involving the follicle-stimulating hormone receptor. Epidemiological data remain mixed, suggesting that dietary consumption and circulating lipid biomarkers are critical factors. This review explores the dual and interconnected roles of omega-3 and omega-6 polyunsaturated fatty acids in ovarian cancer, detailing their molecular mechanisms, implications for metabolic therapy, and potential for advanced combination strategies.