PCK1 (phosphoenolpyruvate carboxykinase 1) is a cytosolic enzyme that catalyzes the reversible conversion of oxaloacetate to phosphoenolpyruvate, serving as the rate-limiting enzyme in gluconeogenesis and regulating glucose homeostasis 1. Beyond its canonical metabolic role, PCK1 functions as a protein kinase when phosphorylated at Ser-90 by AKT1, translocating to the endoplasmic reticulum where it phosphorylates INSIG proteins using GTP as a donor 2. This kinase activity disrupts INSIG-SCAP interactions, promoting SREBP nuclear translocation and lipogenesis activation, particularly in hepatocellular carcinoma (HCC) cells 2. PCK1 is downregulated in HCC, where its deficiency promotes disease progression through multiple mechanisms. Loss of PCK1 enhances hexosamine biosynthesis pathway activity and protein O-GlcNAcylation under glucose deprivation, promoting CHK2-mediated cell proliferation 3. Additionally, PCK1 depletion impairs S-adenosylmethionine biosynthesis, reducing H3K9me3 modifications and allowing oncogene S100A11 activation 4. Conversely, intermittent fasting upregulates hepatic PCK1 alongside PPARα, cooperatively ameliorating non-alcoholic steatohepatitis (NASH) and blunting HCC development 5. PCK1 is identified as a core regulatory gene in aflatoxin B1-induced hepatocarcinogenesis 6. These findings establish PCK1 as a metabolic tumor suppressor with multifaceted roles beyond gluconeogenesis.