FBXO3 (F-box protein 3) is a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes that regulates protein degradation through the ubiquitin-proteasome system 1. Primary function: FBXO3 assembles into SCFFBXO3 complexes via F-box domain interactions with SKP1 and CUL1 2, enabling recognition and ubiquitination of target proteins for proteasomal degradation. Mechanism: During viral infection, FBXO3 associates with Rift Valley fever virus NSs protein to form a remodeled filamentous E3 ligase that targets the TFIIH complex, inhibiting antiviral immunity 3. In cellular homeostasis, TBK1-dependent phosphorylation of FBXO3 facilitates TMEM192 ubiquitination to activate lysophagy, a process eliminating damaged lysosomes 45. Disease relevance: FBXO3 upregulation contributes to neuroinflammation in cerebral ischemia/reperfusion injury through HIPK2 degradation 6. Elevated FBXO3 expression correlates with poor outcomes in rheumatoid arthritis, leukemia, and oral squamous cell carcinoma 1. In breast cancer, FBXO3 stabilizes USP4 to promote PI3K-mediated metastasis 7. Clinical significance: FBXO3 represents a therapeutic target for inflammatory diseases, ischemic stroke, and malignancies, with potential for small-molecule inhibition to modulate disease progression.