SLC37A4 encodes a glucose-6-phosphate transporter localized to the endoplasmic reticulum that functions as an inorganic phosphate and glucose-6-phosphate antiporter 1. It transports cytoplasmic glucose-6-phosphate into the endoplasmic reticulum lumen while facilitating phosphate efflux, working in conjunction with glucose-6-phosphatase to enable glucose production through glycogenolysis and gluconeogenesis, thereby maintaining blood glucose homeostasis 23. Mutations in SLC37A4 cause glycogen storage disease type 1b (GSD1b), characterized by excessive glycogen and fat accumulation in liver, kidney, and intestinal tissues, resulting in hypoglycemia, hepatomegaly, growth retardation, lactic acidemia, and hyperlipidemia 23. GSD1b patients uniquely develop neutropenia and impaired neutrophil function leading to increased infections and inflammatory bowel disease 24. Mechanistically, G6PT deficiency promotes glycolysis and lactate accumulation in macrophages, which suppresses NLRP3 inflammasome activation through lactylation-driven ALKBH5 upregulation, impairing antimicrobial immunity 5. Rare heterozygous SLC37A4 mutations cause congenital disorders of glycosylation type 2W (SLC37A4-CDG) through transporter mislocalization to the Golgi 6. Beyond metabolic disease, aberrant SLC37A4 splicing promotes oral cancer progression and chemotherapy resistance 7.