G6PC1 (glucose-6-phosphatase catalytic subunit 1) is a key endoplasmic reticulum membrane enzyme that catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate 1. This reaction represents the terminal step of both gluconeogenesis and glycogenolysis, making G6PC1 essential for blood glucose homeostasis 2. G6PC1 functions as part of a complex with the glucose-6-phosphate transporter SLC37A4 to complete hepatic glucose production 3. Mutations in G6PC1 cause glycogen storage disease type 1a (GSD-1a), a rare autosomal recessive carbohydrate metabolism disorder characterized by chr17 hypoglycemia, hepatomegaly, and glycogen accumulation 14. Aberrant G6PC1 function also leads to increased fasting blood glucose 1. Recently, DTX401, an AAV8-mediated gene therapy expressing G6PC1, demonstrated clinical efficacy in GSD-1a patients, reducing daily cornstarch requirements by 68% and increasing time to hypoglycemia during fasting challenges 2. Beyond classical glycogen storage disease, G6PC1 expression abnormalities are implicated in hepatocellular carcinoma pathogenesis, with low G6PC1 expression correlating with poor prognosis and involvement in metabolic reprogramming 5. G6PC1 inhibitors represent potential therapeutics for reducing fasting blood glucose without adverse glucocorticoid signaling effects 67.