GYS2 (glycogen synthase 2) catalyzes hepatic glycogen biosynthesis by transferring glucose units from UDP-glucose to the non-reducing end of alpha-1,4-glucan chains, extending glycogen primers initiated by glycogenin 1. Beyond its metabolic role, GYS2 functions as a tumor suppressor through a negative feedback loop with p53; GYS2 competitively binds MDM2 to prevent p53 ubiquitination and degradation, while p53 simultaneously represses GYS2 transcription, creating a circuit that maintains cellular homeostasis and restricts hepatocellular carcinoma (HCC) progression 23. GYS2 is a BMAL1-regulated circadian gene whose rhythmic expression patterns are disrupted in liver disease progression, and GYS2 overexpression inhibits HepG2 cell proliferation and migration while elevating p53 expression 4. Additionally, GYS2 represents one of several glycolytic negative regulators inversely associated with the Warburg effect in HCC 5. Mutations in GYS2 cause glycogen storage disease type 0 (GSD0), a rare autosomal recessive disorder characterized by hepatic glycogen synthase deficiency, hyperketotic hypoglycemia, and neurocognitive complications that can be managed through dietary intervention 16. GYS2 also participates in glycogen metabolic reprogramming that supports M2 macrophage polarization and thermogenic remodeling of adipocytes 78.