USPL1 (ubiquitin-specific peptidase-like 1) is a SUMO-specific isopeptidase that catalyzes protein desumoylation with selective affinity for SUMO2 and SUMO3 over SUMO1 1. It also processes full-length SUMO proteins to their mature forms 2. Unlike other deubiquitinating enzymes, USPL1 neither binds nor cleaves ubiquitin 2. Mechanistically, USPL1 functions as a component of Cajal body complexes that directly associate with U snRNA loci 3. It plays a critical role in RNA polymerase II-mediated snRNA transcription by interacting with the Little Elongation Complex; USPL1 knockdown reduces snRNA levels and impairs subsequent snRNP assembly and pre-mRNA splicing 3. Beyond its catalytic function, USPL1 possesses essential non-catalytic roles in Cajal body organization and cell proliferation independent of its enzymatic activity 2. Clinically, genetic variation in USPL1 shows disease relevance: the rs7984952 variant associates with reduced risk of Grade 3 breast tumors, with increased USPL1 expression in tumor tissue correlating with the protective C allele 4. USPL1 is upregulated in heat stress responses 5 and implicated in multiple myeloma pathogenesis through miR-148a-USPL1 regulatory networks 6. As an incompletely characterized deubiquitinating enzyme, USPL1 represents a promising therapeutic target for cancer 7.