NEURL1 is an E3 ubiquitin ligase that functions as a tumor suppressor through multiple mechanistic pathways. Functionally, NEURL1 acts as a plasma membrane-localized ubiquitin ligase that directly ubiquitinates the Notch ligand Jagged1, promoting its endocytosis and degradation 1. This ubiquitination activity inhibits Notch signaling by reducing expression of downstream targets HES1 and HEY1 2. NEURL1 also ubiquitinates and promotes proteasomal degradation of PDE9A, a cGMP-specific phosphodiesterase 3. In disease contexts, NEURL1 is significantly downregulated in medulloblastoma tumors, particularly hedgehog-activated subtypes, with restored expression inducing apoptosis and suppressing tumor growth and colony formation 2. Similarly, NEURL1 is downregulated in bladder cancer, where overexpression inhibits cell proliferation, increases apoptosis, and sensitizes cells to cisplatin through PDE9A degradation 4. Clinically, genetic variants in NEURL1 (rs6584555) associate with atrial fibrillation, particularly sinus venosus-derived triggers, suggesting cardiac rhythm regulation 5. Additionally, neuritin negatively regulates NEURL1 activity by promoting its proteasomal degradation and weakening its substrate affinity, providing a mechanism to modulate Notch pathway signaling during neural development 6. Overall, NEURL1 emerges as a multi-functional tumor suppressor operating primarily through Notch pathway inhibition and selective substrate ubiquitination.