Metabolism-driven chemoresistance in ovarian cancer: molecular mechanisms and emerging therapeutic strategies

Ovarian cancer remains highly lethal despite advances in surgery, chemotherapy, and maintenance therapy, largely because many patients are diagnosed at an advanced stage and recurrent tumors frequently acquire resistance to platinum and taxane-based chemotherapy. Classical resistance mechanisms, including enhanced DNA repair, reduced drug accumulation, apoptosis evasion, and cell plasticity, are increasingly linked to metabolic adaptation. Under therapeutic pressure, ovarian cancer cells adjust mitochondrial respiration, glycolysis, lipid utilization, and antioxidant defenses to maintain DNA repair capacity, membrane integrity, and stress tolerance. This review discusses the contribution of energy metabolism, lipid remodeling, ferroptosis, and cuproptosis to ovarian cancer chemoresistance. Rather than representing a single fixed phenotype, resistant tumors may show distinct metabolic and cell-death states, such as glycolysis-dominant, mitochondria-dependent, lipid-adapted, ferroptosis-resistant, or cuproptosis-sensitive states, which change during chemotherapy, recurrence, and microenvironmental selection. Defining these features may help guide biologically informed treatment strategies for ovarian cancer, moving therapeutic design away from broadly applied combinations toward more rational and individualized approaches.