PDK1 is a mitochondrial kinase that serves as a critical metabolic switch regulating glucose and fatty acid metabolism by phosphorylating pyruvate dehydrogenase (PDH), thereby inhibiting its activity and suppressing acetyl-CoA formation 1. This mechanism reduces flux through the tricarboxylic acid cycle and shifts metabolism from oxidative phosphorylation toward glycolysis. PDK1 plays a central role in cellular adaptation to hypoxia, with HIF-1α directly transactivating the PDK1 gene to promote ATP production while attenuating hypoxic reactive oxygen species generation 1. Under hypoxic conditions, PDK1 activation prevents apoptosis by maintaining cellular energy levels. In cancer biology, PDK1 functions as an oncogenic driver through multiple pathways: HIF-1α-mediated PDK1 activation confers cuproptosis resistance by reducing lipoylated enzyme expression 2, while copper-bound PDK1 promotes Akt signaling to activate Wnt/β-catenin pathways and cancer stem cell properties 3. PDK1 also mediates drug resistance through EGFR/AKT/HIF-1α axis activation in NSCLC 4 and enables PI3K-Akt signaling in KRAS-mutant colorectal cancer via neddylation-dependent mechanisms 5. Beyond cancer, PDK1 dysfunction contributes to cardiovascular pathology, with PDK1 knockout in cardiomyocytes increasing hypoxia-induced apoptosis through mitochondrial dysregulation and elevated oxidative stress 6. PDK1 inhibition emerges as a therapeutic strategy across multiple disease contexts.