Dichloroacetate reprograms metabolism and disrupts ROS adaptation, attenuating stemness to reverse chemoresistance in ovarian cancer

Chemotherapy resistance and the associated high rates of relapse represent critical barriers in the effective management of ovarian cancer, contributing significantly to poor patient prognosis and mortality. In this study, we investigated the therapeutic potential of Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase (PDK) inhibitor, as a strategy to overcome Cisplatin (CP) resistance. We initially identified that CP-resistant ovarian cancer cells exhibit elevated phosphorylation of pyruvate dehydrogenase (pPDH). Treatment with DCA effectively blocked pPDH, leading to a marked suppression of cell migration and invasion through the reversion of motile mesenchymal phenotypes to epithelial characteristics. Furthermore, DCA treatment significantly attenuated stem cell-like properties, as evidenced by reduced sphere formation capacity. When combined with CP, DCA exerted a synergistic anti-proliferative effect by triggering apoptosis in chemoresistant cells. Mechanistic investigations revealed a distinct metabolic adaptation: while CP induces cell death via Reactive Oxygen Species (ROS) generation in sensitive cells, resistant cells display high basal ROS levels and fail to generate further ROS upon CP exposure. Crucially, DCA treatment disrupted this ROS adaptation, inducing a lethal accumulation of ROS specifically in the resistant cells. Collectively, our findings indicate that DCA restores CP sensitivity by targeting ROS metabolism and inhibiting stemness, suggesting it is a promising therapeutic candidate for treating refractory ovarian cancer.