FBP1 (fructose-1,6-bisphosphatase 1) is a key gluconeogenic enzyme that catalyzes the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, serving as a rate-limiting step in gluconeogenesis 1. Beyond its enzymatic function, FBP1 acts as a critical tumor suppressor through multiple mechanisms. It forms a complex with AKT, PP2A-C, and aldolase B to prevent insulin hyperresponsiveness by accelerating AKT dephosphorylation, maintaining glucose and lipid homeostasis 1. FBP1 also directly dephosphorylates telomerase reverse transcriptase (TERT) at Ser227, inhibiting telomerase activity and promoting cellular senescence 2. In hepatocellular carcinoma (HCC), FBP1 is universally silenced and functions as a metabolic tumor suppressor 3. Loss of FBP1 promotes HCC evolution from senescent hepatocytes by enabling AKT and NRF2 activation, which accelerates p53 degradation and enhances proliferation of cancer progenitor cells 4. FBP1 deficiency also disrupts liver metabolism, promoting hepatic stellate cell activation and creating a pro-tumorigenic microenvironment 3. Additionally, FBP1 plays roles in immune regulation, with elevated expression in macrophages supporting granuloma formation in sarcoidosis 5 and enabling glyconeogenesis in inflammatory macrophages 6.