GCKR encodes glucokinase regulator protein (GKRP), a key modulator of hepatic glucose metabolism and a pleiotropic locus in metabolic disease. Functionally, GCKR regulates glucokinase by forming an inactive cytoplasmic complex with this enzyme and promoting its nuclear localization, thereby sequestering a reserve pool of glucokinase that can be rapidly mobilized postprandially 12. This inhibitory interaction is dynamically regulated by fructose metabolites: fructose 6-phosphate increases GCKR-glucokinase affinity, while fructose 1-phosphate strongly decreases it 12. Recent mechanistic studies reveal that GCKR variants influence hepatic reductive stress (NADH/NAD+ ratio), which activates the transcription factor ChR2 and orchestrates metabolic traits including hepatic steatosis, circulating FGF21, and acylglycerol species 3. Clinically, GCKR variants are among the most strongly associated genetic factors with non-alcoholic fatty liver disease (NAFLD) across diverse populations 45. The GCKR-rs1260326 T allele elevates NASH severity specifically in diabetic individuals but provides protection from fibrosis in non-diabetic states, highlighting metabolic state-dependent genotype-phenotype relationships 6. Individuals carrying high-risk GCKR variants show 2.5–6-fold increased risk of NAFLD progression, cirrhosis, and hepatocellular carcinoma 47.