RBX1 (ring-box 1) is a core component of cullin-RING-based E3 ubiquitin-protein ligase (CRL) complexes that mediate the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction, and transcription 1. As an essential subunit, RBX1 functions within multiple CRL complexes including CRL4-CRBN, where it forms part of the E3 ubiquitin ligase that can be modulated by drugs like thalidomide and lenalidomide 21. The protein recruits E2 ubiquitin-conjugating enzymes and facilitates substrate ubiquitination, with its activity being critical for CRL function 3. RBX1 promotes neddylation of cullins, which is essential for CRL activation and proper conformation for substrate access 3. In disease contexts, RBX1-containing complexes are therapeutically targeted in cancer treatment, particularly in multiple myeloma where lenalidomide modulates CRL4-CRBN activity to degrade specific transcription factors like IKZF1 and IKZF3 4. The protein also participates in cellular stress responses, including DNA damage response and oxidative stress management through its role in various CRL complexes 5. RBX1's function is fundamental to maintaining cellular homeostasis through regulated protein degradation pathways.