PCK2 encodes mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), a key metabolic enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in gluconeogenesis and glyceroneogenesis 1. Beyond its classical metabolic role, PCK2 functions as a serine/threonine kinase that phosphorylates ACSL4 at T679, promoting ferroptosis-associated phospholipid remodeling 2. The enzyme's activity is regulated by lactylation at Lys100, which enhances its kinase function and contributes to hepatic ferroptosis during ischemia-reperfusion injury 3. PCK2 also supports glyconeogenesis from glutamine, lactate, and glycerol in inflammatory macrophages, enabling cellular functions in nutrient-poor environments 4. In cancer, PCK2 promotes tumor progression through multiple mechanisms: it activates TGF-β/SMAD3 signaling by preventing TRIM67-mediated SMAD3 ubiquitination, enhancing epithelial-to-mesenchymal transition in triple-negative breast cancer 5, and contributes to lenvatinib resistance in hepatocellular carcinoma through metabolic reprogramming 6. Notably, tumor-repopulating cells downregulate PCK2 to evade ferroptosis and maintain therapy resistance 2. Genetic variants in PCK2 are associated with multi-organ fibrosis, and deficiency causes mitochondrial phosphoenolpyruvate carboxykinase deficiency 7.