FBXL14 is an F-box protein that functions as the substrate-recognition component of SCF-type E3 ubiquitin-protein ligase complexes, directing the polyubiquitination and proteasomal degradation of multiple substrates. Beyond its canonical target SNAI1, FBXL14 regulates protein stability of c-Myc, HES1, CDCP1, RPA194, and DUSP6, positioning it at the intersection of cell proliferation, differentiation, and stress responses 1 2 3 4. FBXL14 is hypoxia-sensitive; its expression is suppressed during hypoxia, allowing SNAI1 accumulation and epithelial-to-mesenchymal transition 5. In cancer cells, FBXL14-mediated c-Myc degradation can inhibit glioblastoma stem cell self-renewal, and its suppression by the deubiquitinase USP13 maintains oncogenic c-Myc levels 2. However, recent evidence suggests metabolic factors modulate this pathway: β-hydroxybutyrylation of SNAI1 can prevent FBXL14-mediated degradation and promote pancreatic cancer metastasis 6. In non-malignant contexts, FBXL14 suppresses foam cell formation and atherosclerosis progression in ApoE-/- mice by promoting DUSP6 ubiquitination and NRF2 pathway activation 7. These findings suggest FBXL14 inhibition—via targeting β-hydroxybutyrylation or upstream regulators—may represent a therapeutic strategy in metastatic cancer, while FBXL14 activation could address atherosclerosis-related complications.