FBXO6 is an F-box protein that functions as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, mediating the recognition and ubiquitination of glycosylated protein substrates. Its primary role involves ERAD pathway function, where it recognizes N-glycan chains on misfolded glycoproteins retrotranslocated to the cytosol, promoting their proteasomal degradation 1. FBXO6 operates through N-glycan-dependent substrate recognition; it can bind both high-mannose and complex-type oligosaccharides, and recently identified non-canonical mechanisms include cooperation with RBR-type E3 ligase ARIH1 to generate atypical ubiquitin chains on N-GlcNAc residues 2. Beyond ERAD, FBXO6 participates in cell cycle regulation by interacting with spindle checkpoint proteins Mad2 and BubR1, though overexpression induces premature mitotic exit and chr1 instability 3. Disease relevance is substantial: FBXO6 regulates multiple pathologically important substrates including Ero1L (ER stress-induced apoptosis) 1, RNASET2 (ovarian cancer development) 4, MMP14 (osteoarthritis progression) 5, and NLRX1 (antiviral immunity in influenza) 6. Therapeutically, FBXO6 upregulation protects cartilage through MMP14 degradation 5, and FBXO6 gene delivery via polymeric vectors ameliorates osteoarthritis in animal models 7. FBXO6 expression is frequently dysregulated in cancer, with elevated levels correlating with poor prognosis in ovarian cancer.