CUL3 (cullin 3) is a scaffold protein that forms the core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes, which mediate ubiquitination and subsequent proteasomal degradation of target proteins 1. The functional specificity of CUL3 complexes depends on BTB domain-containing adaptor proteins that provide substrate recognition. CUL3 regulates diverse cellular processes through substrate-specific complexes: CUL3-KLHL3 controls ion transport by ubiquitinating WNK4 kinases in the kidney 2, CUL3-LZTR1 regulates RAS signaling by promoting RAS ubiquitination at lysine-170 and attenuating membrane association 34, and CUL3-ARMC5 mediates transcriptional quality control by ubiquitinating RNA polymerase II subunits 5. CUL3 also controls autophagy through BECN1 degradation 1, facilitates transcription-replication conflict resolution via KCTD10 6, and can be hijacked by bacterial pathogens to modulate host mitophagy 7. Disease relevance includes familial hyperkalemic hypertension caused by CUL3 mutations that disrupt WNK kinase regulation 2, and Noonan syndrome through LZTR1 mutations affecting RAS regulation 4. CUL3 also shows therapeutic potential as a target in cancer drug resistance 8.