SIRT4 is a mitochondrial NAD-dependent enzyme with diverse catalytic activities that primarily functions as a metabolic regulator and tumor suppressor. As a protein lipoamidase and biotinylase, SIRT4 inhibits the pyruvate dehydrogenase complex by removing lipoamide cofactors from DLAT 1. Through ADP-ribosylation of mitochondrial GLUD1, SIRT4 suppresses glutamine metabolism and anaplerosis, promoting cell cycle arrest in response to DNA damage 23. SIRT4 also regulates lipid homeostasis by deacetylating MLYCD and inhibiting PPARA-mediated fatty acid oxidation, while downregulating insulin secretion 43. mTORC1 signaling represses SIRT4 expression to promote proliferation 5. Beyond metabolic control, SIRT4 functions as a tumor suppressor 6 and demonstrates protective roles in acute pancreatitis through HIF-1α/HO-1-mediated ferroptosis inhibition 7. SIRT4 participates in DNA damage response and aging processes, maintaining mitochondrial homeostasis critical for cellular and organismal health 89. The miR-15b-5p-SIRT4 axis regulates endothelial inflammatory responses in sepsis 10. Notably, context-dependent roles exist: SIRT4 promotes pancreatic cancer stemness via ENO1 deacetylation and histone lactylation 11, highlighting SIRT4's complex involvement in both tumor suppression and progression.