PDK4 is a mitochondrial kinase that phosphorylates pyruvate dehydrogenase (PDHA1/PDHA2), thereby inhibiting glucose oxidation and shifting metabolism toward fatty acid utilization 1. This metabolic switch is particularly important during starvation and fasting states for maintaining blood glucose homeostasis and preventing ketone body accumulation. PDK4 expression is dynamically regulated by metabolic and signaling inputs: it is suppressed during endothelial-to-mesenchymal transition 1, downregulated by FGF21-activated PI3K/AKT signaling in cardiac tissue 2, and reduced by dexmedetomidine treatment to improve myocardial recovery 3. Beyond metabolism, PDK4 has emerged as a critical regulator of tissue-specific pathology. PDK4 promotes glucocorticoid-induced skeletal muscle atrophy by phosphorylating and degrading myogenin via the ubiquitin-proteasome system 4, and its expression increases with age in skeletal muscle 5. In cardiac regeneration, PDK4 inhibition shifts cardiomyocytes from fatty acid to glucose oxidation, reducing oxidative stress and promoting proliferation 6. PDK4 also regulates cancer cell glycolysis through m6A mRNA modifications 7. These findings position PDK4 as a multifaceted therapeutic target for metabolic diseases, cardiac dysfunction, muscle wasting, and potentially cancer.