FBXO33 (F-box protein 33) is a substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-ligase complexes that mediates ubiquitination and proteasomal degradation of target proteins 1. The protein recognizes phosphorylated substrates and regulates protein ubiquitination through the ubiquitin-proteasome system 1. Mechanistically, FBXO33 functions as a ubiquitin ligase targeting multiple substrates: it promotes polyubiquitination of p53 at specific lysine residues (K291 and K292) in gallbladder cancer 2, and mediates ubiquitination and degradation of Myc in non-small-cell lung cancer (NSCLC) 3. Additionally, FBXO33 modulates ubiquitination and solubility of polyglutamine disease proteins in spinocerebellar ataxia type 3 (SCA3) pathogenesis 1. Clinically, FBXO33 expression associates with cancer prognosis and progression. In gallbladder cancer, elevated FBXO33 promotes epithelial-mesenchymal transition and metastasis 2, while in NSCLC, reduced FBXO33 correlates with poor overall survival and enhanced stemness characteristics 3. Genome-wide association studies have linked FBXO33 variants to chemotherapy-induced peripheral neuropathy 4, adult ADHD persistence 5, and dysregulated blood lipid metabolism 6. These findings establish FBXO33 as a critical regulator of protein degradation with implications for cancer progression, neurodegenerative diseases, and metabolic disorders.