PGK1 (phosphoglycerate kinase 1) catalyzes the first ATP-generating step of glycolysis, reversibly converting 1,3-diphosphoglycerate to 3-phosphoglycerate. Beyond its canonical glycolytic role, PGK1 functions as a multivalent protein kinase: when translocated to the mitochondrion, it phosphorylates pyruvate dehydrogenase kinase 1 (PDHK1) to inhibit the pyruvate dehydrogenase complex, thereby suppressing oxidative phosphorylation and promoting aerobic glycolysis 1. This metabolic switch is central to the Warburg effect and occurs under hypoxia, EGFR activation, and oncogenic Ras/Braf signaling 1. Recently, PGK1 was shown to phosphorylate NLRP3 inflammasome components independently of its glycolytic activity, regulating inflammatory responses 2. Post-translational modifications of PGK1—including O-GlcNAcylation, crotonylation, succinylation, and arginine methylation—fine-tune its dual roles in coordinating glycolysis and mitochondrial metabolism 3, 4, 5, 6. In cancer, elevated PGK1 activity and phosphorylation correlate with poor prognosis across multiple tumor types including glioblastoma, colorectal cancer, breast cancer, and esophageal squamous cell carcinoma 7, 8, 6. Conversely, enhancing PGK1 activity via terazosin shows neuroprotective effects in Parkinson's disease models and human databases, slowing neurodegeneration 9. These findings establish PGK1 as a metabolic hub with context-dependent therapeutic potential.