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We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evalua