SENP1 is a SUMO-specific protease that catalyzes two essential functions in cellular SUMOylation: maturation of SUMO propeptides (SUMO1, SUMO2, SUMO3) to their active forms, and deconjugation of SUMO from target proteins. This desumoylation activity regulates diverse cellular processes including transcription, metabolism, and DNA damage response. SENP1 deconjugates SUMO from multiple substrates including transcriptional regulators (HDAC1, CLOCK, BHLHE40) and metabolic enzymes, modulating their activities. In response to metabolic stress, SENP1 translocates to mitochondria to activate Sirt3 via desumoylation, enhancing fatty acid oxidation during fasting 1. SENP1 also regulates mitochondrial integrity under hypoxic stress by desumoylating FIS1, maintaining endothelial function and protecting against pulmonary hypertension 2. The enzyme inhibits m6A RNA methylation through desumoylation of METTL3 and ALKBH5. Pathologically, SENP1 is frequently upregulated in cancers and promotes tumorigenesis through multiple mechanisms: in gastric cancer, it drives glycolysis and cisplatin resistance by desumoylating ENO1 3; in colon cancer, it promotes DNA damage repair and chemotherapy resistance by desumoylating RNF168 and preventing phase separation 4. SENP1 inhibitors such as Momordin Ic show promise as therapeutic agents, particularly in combination with conventional chemotherapy.