Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).

Cisplatin resistance remains a primary obstacle in oncology, leading to therapeutic failure and disease recurrence. While resistance mechanisms are multifactorial, metabolic reprogramming has emerged as a critical adaptive strategy for cancer cells to evade cisplatin-induced cytotoxicity. This review synthesizes current evidence on how altered metabolism drives cisplatin resistance, with a particular emphasis on the pivotal role of pyruvate dehydrogenase kinases (PDKs). PDKs act as metabolic gatekeepers by inhibiting the pyruvate dehydrogenase complex (PDHC), diverting glucose flux away from mitochondrial oxidation toward glycolysis. This switch supports biomass production, maintains redox homeostasis, and dampens reactive oxygen species (ROS) generation, ultimately promoting cell survival. We detail how each PDK isoform (PDK1-4) contributes to resistance through distinct mechanisms, including the regulation of the DNA damage response, cancer stemness, and hypoxia signaling. Furthermore, we discuss the metabolic cues that regulate PDK activity and the role of tumor immune metabolism in cisplatin resistance. Furthermore, we discuss the metabolic cues that regulate PDK activity and the emerging role of tumor immunometabolism in the development of cisplatin resistance. Finally, we highlight the therapeutic potential of targeting PDKs, particularly through pharmacological inhibitors such as dichloroacetate (DCA), while also considering the current challenges associated with PDK-directed therapies. Overall, targeting PDK-mediated metabolic plasticity may offer a promising strategy to overcome cisplatin resistance and improve therapeutic outcomes.