Alpha-ketoglutarate alleviates acute pancreatitis by restoring energy metabolism.

Acute pancreatitis (AP) lacks specific therapies. This study identified dysregulated metabolites in AP and investigated the therapeutic potential of α-ketoglutaric acid (AKG). Metabolomic profiling of human serum revealed 76 AP-specific metabolites compared to acute cholecystitis and normal control, with AKG significantly elevated and correlated with disease severity. In a severe AP mouse model, oral AKG supplementation attenuated pancreatic injury, systemic inflammation, and multi-organ damage. Mechanistically, AKG restored pancreatic energy metabolism and mitochondrial structure while reactivating the Nrf2 antioxidant and adenosine monophosphate-activated protein kinase signaling pathways. These findings highlight AKG as a specific metabolic signature of AP and a promising therapeutic agent for alleviating mitochondrial dysfunction and organ injury.