FBXL14 is an F-box protein component of SCF-type E3 ubiquitin ligase complexes that mediates substrate recognition and ubiquitin-dependent degradation of multiple target proteins 1. As a substrate adaptor, FBXL14 directly recognizes and facilitates polyubiquitination of its protein targets, leading to their proteasomal degradation 2. Mechanistically, FBXL14 functions within SCF ubiquitin ligase complexes by binding target proteins through specific recognition motifs and recruiting the ubiquitination machinery. Validated substrates include SNAIL1 2, c-Myc 3, HES1 4, RPA194 (RNA Polymerase I catalytic subunit) 5, CDCP1 6, and DUSP6 7. Notably, SNAIL1 ubiquitination by FBXL14 occurs independently of GSK-3β phosphorylation 2, though β-hydroxybutyrylation of SNAIL1 at lysine 152 blocks FBXL14-mediated degradation 1. Clinically, FBXL14-mediated degradation of specific substrates suppresses cancer progression and metastasis. In pancreatic cancer, preventing FBXL14-mediated SNAIL1 degradation promotes metastatic capacity 1. In glioblastoma, FBXL14-mediated c-Myc degradation inhibits glioma stem cell self-renewal and tumor growth 3. In breast cancer, FBXL14-mediated CDCP1 degradation suppresses metastatic potential 6. Additionally, FBXL14 activation of NRF2 signaling through DUSP6 ubiquitination inhibits atherosclerosis progression 7.