FBXO28 is an F-box protein functioning as a substrate-recognition component of SCF (SKP1-CUL1-F-box)-type E3 ubiquitin ligase complexes 1. It promotes ubiquitination and proteasomal degradation of multiple substrates including TOP2A, SMARCC2, SNAI2, and RAB27A, while also undergoing self-ubiquitination 2341. FBXO28 regulates topoisomerase IIα decatenation activity and maintains genomic stability 2. It plays essential roles in spindle morphology and actin-based spindle migration through ARPC2/ARP3 signaling during oocyte meiosis 5. Clinically, FBXO28 mutations cause developmental and epileptic encephalopathy (DEE-100), characterized by profound intellectual disability, drug-resistant seizures (median onset 22.5 months), movement disorders, and hypotonia 6. Loss-of-function FBXO28 variants account for 1q41-q42 microdeletion syndrome features 7. Conversely, FBXO28 upregulation promotes pancreatic cancer progression via SMARCC2 degradation and inhibits hepatocellular carcinoma metastasis through SNAI2 degradation, suggesting context-dependent oncogenic versus tumor-suppressive functions 34. F-box protein dysregulation contributes to cardiac pathology 8.