UBE2NL is an X-chrX-localized ubiquitin-conjugating enzyme E2-like protein with emerging roles in cancer progression and disease susceptibility. Functionally, UBE2NL possesses ubiquitin conjugating enzyme activity and participates in protein K63-linked ubiquitination and polyubiquitination pathways 1. The protein localizes to the nucleus and associates with extracellular exosomes, facilitating intercellular communication 1. In cancer biology, UBE2NL represents a significant oncogenic factor. When packaged in extracellular vesicles derived from aggressive epithelial ovarian cancer and mesenchymal stromal cells, UBE2NL promotes tumor cell invasiveness and metastasis; conversely, UBE2NL knockdown reduces invasiveness and extends survival in murine models 1. High UBE2NL expression correlates with advanced tumor stages and poor overall survival in ovarian cancer 1. Beyond cancer, UBE2NL variants associate with multiple disease phenotypes. Rare non-synonymous mutations in UBE2NL have been identified in familial gastroschisis, suggesting involvement in developmental pathways regulating blood vessel development and epithelial cell junction assembly 2. UBE2NL mutations also appear in migraine without aura populations, potentially regulating cellular responses to serotonin 3, and X-chromosome X in UBE2NL are enriched in sporadic Alzheimer disease patients, implicating the ubiquitin pathway in neurodegeneration 4. UBE2NL shows promise as both a prognostic biomarker and therapeutic target in cancer.