PDK3 (pyruvate dehydrogenase kinase 3) is a mitochondrial serine/threonine kinase that inhibits pyruvate dehydrogenase activity through phosphorylation of the E1 subunit PDHA1, thereby regulating glucose metabolism and aerobic respiration [UniProt]. The enzyme decreases glucose utilization and increases fat metabolism during prolonged fasting and adaptation to high-fat diets, playing a critical role in glucose homeostasis [UniProt]. PDK3 also contributes to reactive oxygen species generation [UniProt]. In cancer metabolism, PDK3 emerges as a key metabolic regulator. NCAPD3 recruits E2F1 to PDK3 promoter regions, upregulating PDK3 expression and inhibiting pyruvate dehydrogenase (PDH) activity and the TCA cycle, thereby enhancing aerobic glycolysis in colorectal cancer 1. In cancer cachexia, IL-6-JAK-STAT signaling induces hepatic PDK3 expression, driving gluconeogenesis and contributing to tumor-induced metabolic dysregulation 2. PDK3 downregulation suppresses glycolysis and reduces tumor growth in head and neck cancer models 3. Clinically, PDK3 mutations cause X-linked dominant Charcot-Marie-Tooth disease type 6 [NCBI Summary]. A chromosome X;13 balanced translocation disrupted PDK3 function through distinct molecular mechanisms requiring multi-omic integration to resolve the associated Mendelian condition 4. These findings identify PDK3 as both a metabolic regulator and a disease-associated gene with implications for cancer and neuromuscular disorders.