SENP2 (SUMO specific peptidase 2) is a critical desumoylating enzyme that regulates cellular homeostasis and disease processes through removal of Small Ubiquitin-like Modifier (SUMO) proteins from target substrates. SENP2 catalyzes desumoylation by cleaving SUMO proteins from lysine residues on target proteins, thereby modulating their stability, localization, and function 1. In metabolic regulation, SENP2 controls energy homeostasis in human adipocytes and skeletal muscle cells, where knockdown reduces glucose metabolism and lipid accumulation while increasing lipid oxidation 2. SENP2 is essential for insulin signaling in human skeletal muscle, as its depletion completely abolishes insulin-stimulated glycogen synthesis and Akt phosphorylation 3. In cardiovascular protection, SENP2 prevents ferroptosis during myocardial ischemia-reperfusion injury by desumoylating NCOA4, which stabilizes the protein and reduces ferritinophagy-dependent cell death 4. SENP2 also regulates epithelial cell fate by controlling the mitosis-differentiation checkpoint through its localization to mitotic spindles, where loss causes mitotic defects and premature differentiation 5. Additionally, SENP2 modulates DNA damage responses by stabilizing hSSB1 through desumoylation, enhancing recruitment of DNA repair complexes 1. Clinical significance includes potential therapeutic targeting in cancer, metabolic disorders, and cardiovascular disease.