SIRT5 is a mitochondrial NAD-dependent protein desuccinylase, demalonylase, and deglutarylase that regulates diverse metabolic and cellular processes 1. Its primary function is removing post-translational modifications from target proteins to modulate their activity. SIRT5 activates carbamoyl phosphate synthetase 1 (CPS1) through desuccinylation, regulating ammonia detoxification during fasting 2. Beyond the liver, SIRT5 controls ammonia production in non-hepatic cells by desuccinylating glutaminase, thereby modulating glutamine metabolism and ammonia-induced autophagy 2. SIRT5 also enhances fatty acid oxidation in diabetic cardiomyopathy by desuccinylating carnitine palmitoyltransferase 2 (CPT2), preventing lipotoxic accumulation 3. Emerging evidence demonstrates SIRT5's role in age-related muscle degeneration through desuccinylation of TBK1, suppressing inflammation-associated senescence 4. In cancer contexts, SIRT5 promotes colorectal cancer progression via ME2 desuccinylation, enhancing mitochondrial respiration under glutamine deprivation 5, while SIRT5 loss in hepatocellular carcinoma promotes an immunosuppressive tumor microenvironment through bile acid dysmetabolism 6. SIRT5 represents a metabolic checkpoint integrating nutrient sensing with cellular homeostasis and aging, offering therapeutic targets for metabolic diseases and cancer.