NEURL1B (neuralized E3 ubiquitin protein ligase 1B) is an E3 ubiquitin ligase that regulates the Notch signaling pathway through ubiquitin-dependent modifications of Notch ligands. The protein localizes to the cytosol and early endosomes, where it catalyzes ubiquitination of key pathway components 1. Mechanistically, NEURL1B modulates DLL1 stability by controlling its ubiquitination state, thereby regulating Notch pathway activation 1. In hepatocellular carcinoma (HCC), NEURL1B promotes tumor proliferation and migration, with genetic variants (rs4868192) associated with altered HCC survival outcomes, and notably, the protective C allele correlates with reduced NEURL1B mRNA expression 2. Beyond HCC, NEURL1B dysregulation appears relevant to multiple diseases: it interacts with ANGPTL4 in pathological retinal neovascularization during retinopathy of prematurity 3, associates with pelvic organ prolapse severity through gene-environment interactions 4, participates in granulosa cell dysfunction in primary ovarian insufficiency 5, and relates to early brain metastasis risk in lung adenocarcinoma 6. NEURL1B expression also shows sex- and APOE-genotype-specific patterns in Alzheimer's disease white matter vulnerability 7. Therapeutically, NEURL1B represents a promising drug target, with compounds directly targeting and degrading NEURL1B demonstrating significant anti-HCC efficacy comparable to sorafenib 1.