UFSP2 is a thiol-dependent isopeptidase that functions as the primary deUFMylating enzyme, specifically cleaving UFM1 (ubiquitin-fold modifier 1) from conjugated target proteins 1. The enzyme acts on multiple substrates including PD-L1, MRE11, ribosomal protein RPL26, and TRIP4, playing crucial roles in diverse cellular processes 23. UFSP2 mediates critical regulatory functions including PD-L1 destabilization through enhanced ubiquitination, which impacts tumor immune evasion 2, and DNA replication fork stability by modulating MRE11-mediated fork degradation in BRCA1/2-deficient cells 3. The enzyme also facilitates ribosome recycling from the endoplasmic reticulum by deUFMylating RPL26 1. Disease relevance is significant, as pathogenic UFSP2 variants cause distinct disorders: homozygous variants (e.g., V115E) result in severe neurodevelopmental disabilities and epilepsy with impaired deUFMylation activity 1, while heterozygous variants cause autosomal dominant spondyloepimetaphyseal dysplasia 4. In Alzheimer's disease, reduced UFSP2 levels correlate with hyperUFMylation and pathological tau accumulation 5. UFSP2 represents a potential therapeutic target, as covalent inhibitors can enhance UFMylation activity for combination cancer immunotherapy 2.