PGM2L1 (phosphoglucomutase 2 like 1) is a glucose-1,6-bisphosphate (G-1,6-BP) synthase that catalyzes the synthesis of G-1,6-BP using 1,3-bisphosphoglycerate as a phosphate donor and various 1-phosphate sugars as acceptors 1. The enzyme is predominantly expressed in brain tissue 1, where G-1,6-BP accumulates to levels exceeding those required for phosphoglucomutase cofactor function, suggesting regulatory roles beyond simple enzymatic support. Mechanistically, PGM2L1-derived G-1,6-BP positively regulates mitochondrial pyruvate uptake via direct interaction with mitochondrial pyruvate carrier (MPC) subunits, thereby coupling glycolysis-derived pyruvate to the tricarboxylic acid cycle and supporting neuronal post-ischemic viability 2. G-1,6-BP levels are dynamically regulated by glycolytic flux, cellular energy state, and upstream signaling cascades 2. In non-neuronal contexts, PGM2L1 co-expression with ENO1 promotes pancreatic cancer proliferation, migration, and glycolytic flux 3, while high PGM2L1 expression correlates with poor prognosis in cholangiocarcinoma and triple-negative breast cancer, where it drives metabolic reprogramming and neutrophil infiltration 45. Clinically, PGM2L1 mutations are associated with neurodevelopmental disorders featuring hypotonia, dysmorphic facies, and skin abnormalities. The enzyme's dual roles in neuroprotection and oncogenic metabolism suggest its potential as a therapeutic target across distinct pathological contexts.