NLE1 (notchless homolog 1) is a nucleolar protein primarily functioning as a ribosome biogenesis factor essential for 60S ribosomal subunit assembly 1. NLE1 interacts with the AAA+ ATPase MDN1 through its ubiquitin-like domain, a mechanism conserved from yeast to humans 21. Beyond ribosomal biogenesis, NLE1 regulates Notch signaling and influences cell cycle progression through CDKN1A expression and Wnt pathway components. In cancer biology, NLE1 emerges as a critical oncogenic driver across multiple malignancies. In colorectal cancer, c-MYC-mediated NLE1 upregulation following SMAD4 loss supports protein biosynthesis and drives tumor growth and metastasis 3. Similarly, NLE1 knockdown inhibits proliferation, migration, and invasion in melanoma and non-small cell lung cancer models 45. In melanoma, NLE1 activates PI3K/AKT signaling, while in NSCLC it additionally operates through E2F1-mediated CDK1 transcription 45. In glioblastoma, the NLE1-Notch1 complex regulates brain tumor stem cell self-renewal; targeting NLE1 with edaravone sensitizes cells to radiotherapy 6. Clinically, elevated NLE1 expression correlates with poor prognosis and advanced disease stages across cancers, predicting overall and relapse-free survival in colorectal cancer 3. NLE1 has emerged as a potential therapeutic target in cancer treatment.