FBXL7 encodes a substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes that mediates ubiquitination and proteasomal degradation of multiple substrates including AURKA, BIRC5, c-SRC, Snail1, and PFKFB4. It plays dual roles across distinct biological contexts. In developmental and lymphatic physiology, biallelic loss-of-function mutations in FBXL7 are associated with Hennekam syndrome, an autosomal recessive disorder characterized by congenital lymphedema, intestinal lymphangiectasia, and facial dysmorphism, suggesting shared pathway function with FAT4 1. In cancer biology, FBXL7 functions primarily as a tumor suppressor: reduced expression correlates with poor prognosis in pancreatic and prostate cancers and promotes epithelial-to-mesenchymal transition and metastasis 2, while elevated FBXL7 opposes glioma progression 3 and correlates with improved outcomes. Epigenetic hypermethylation silences FBXL7 in multiple cancers 24. In hepatocellular carcinoma, FBXL7-mediated PTEN degradation drives metabolic reprogramming and immune evasion 5. Recent evidence suggests FBXL7 dysregulation also influences non-small cell lung cancer glucose metabolism through the EZH2/FBXL7/PFKFB4 axis 6, and a genetic variant (rs75002042) associates with Alzheimer's disease risk in Caribbean Hispanics 7. DNA-demethylating agents like decitabine may restore FBXL7 expression to suppress metastasis 2.