Cisplatin resistance in ovarian cancer: exploration and insights from metal ion homeostasis imbalance

Ovarian cancer remains a lethal gynecological malignancy, and cisplatin resistance is a major therapeutic barrier. Beyond classical mechanisms, dysregulated redox homeostasis is now recognized as a key determinant of cellular fate and chemoresistance. Metabolic reprogramming in cancer cells critically perturbs the cellular redox system, positioning mitochondria—a nexus of metabolism and redox signaling—as a promising therapeutic target for modulating platinum sensitivity. Importantly, metabolic reprogramming involves alterations in mitochondrial homeostasis of the redox-active copper (Cu) and iron (Fe) ions. These ions are fundamental to energy metabolism, and their dysregulation profoundly affects cellular stress responses. Critically, disrupted Cu/Fe homeostasis directly regulates novel cell death pathways: excess Cu induces cuproptosis through the aggregation of lipoylated tricarboxylic acid cycle proteins, whereas aberrant Fe metabolism drives ferroptosis through iron-dependent lipid peroxidation. Therefore, this review focuses on mitochondrial redox regulation and explores the connections among metabolic reprogramming, mitochondrial ion metabolism, and novel modes of programmed cell death in cisplatin-resistant ovarian cancer cells. From an ion-centric perspective, it aims to provide new insights into targeting the mitochondria-mediated redox regulatory network to enhance sensitivity to platinum-based drugs.