SENP5 is a SUMO-specific peptidase that catalyzes two essential functions in the SUMOylation pathway: processing full-length SUMO3 to its mature form and deconjugating SUMO2/3 from target proteins 1. Structurally, SENP5 shows preferential specificity for SUMO2/3 over SUMO1 due to favorable interactions between Arg624 and Asp63 in SUMO2/3 1. SENP5 functions as a nucleolar protein involved in ribosome biogenesis, where its inactivation disturbs 40S and 60S ribosomal subunit assembly and triggers both p53-dependent and p53-independent cell cycle checkpoints through CDK6 downregulation 2. The enzyme plays critical roles in cancer progression through multiple mechanisms: promoting homologous recombination-mediated DNA repair via H2AZ deSUMOylation in colorectal cancer 3, driving breast cancer progression through CDK1 deSUMOylation 4, and enhancing endometrial cancer cell growth by regulating β-catenin deSUMOylation to promote ferroptosis resistance 5. SENP5 also participates in mitochondrial dynamics by counteracting SUMO1 modification of Drp1, thereby regulating mitochondrial fission in various pathological conditions 67. Clinically, elevated SENP5 expression correlates with radiotherapy resistance and poor prognosis in multiple cancer types, suggesting its potential as both a prognostic marker and therapeutic target 345.