HUWE1 is an E3 ubiquitin ligase that catalyzes polyubiquitination and proteasomal degradation of multiple target proteins 1. It regulates apoptosis through MCL1 degradation and modulates DNA repair by monoubiquitinating DNA polymerase beta 2. HUWE1 also ubiquitinates p53 and core histones, contributing to tumor suppression 1. In mitochondrial dynamics, HUWE1 ubiquitinates MFN2 to negatively regulate fusion, and acts as a cofactor for mitophagy-associated ubiquitination with AMBRA1 3. Mechanistically, HUWE1 regulates signaling pathways by mediating assembly of branched Lys-63/Lys-48-linked ubiquitin chains that modulate JNK and NF-κB signaling 4. In oncology, HUWE1-dependent MYC multimerization protects stalled replication forks during DNA damage, enabling tumor cell proliferation 5. HUWE1 also regulates PD-L1 stability by mediating its polyubiquitination, with therapeutic implications for immune checkpoint therapy 6. Disease-relevant mutations in HUWE1 cause X-linked syndromic intellectual disability characterized by developmental delay, speech delay, short stature, and facial dysmorphism 78. HUWE1 variants have been identified as novel driver mutations in multiple myeloma 9, and targeting HUWE1-mediated YEATS4 degradation shows promise for bladder cancer therapy 10.