FBXL20 is an F-box protein that functions as a substrate-recognition component of SCF (SKP1-CUL1-F-box)-type E3 ubiquitin ligase complexes 1. It mediates proteasomal degradation of multiple cellular targets including RIM1 (regulating synaptic membrane exocytosis 1), Vps34, PUMA, BAX, and PR55α 1234. In the nervous system, FBXL20 regulates synaptic vesicle release through RIM1 degradation and participates in DNA damage responses by controlling autophagy via Vps34 ubiquitination in a p53-dependent manner 12. Dysregulation of FBXL20 is implicated in multiple diseases: decreased FBXL20 expression in refractory epilepsy correlates with increased seizure frequency and elevated RIM1 levels 1, while elevated FBXL20 promotes breast cancer progression by degrading pro-apoptotic proteins PUMA and BAX, enhancing chemoresistance 3. In colorectal cancer, FBXL20 overexpression increases cell invasion through E-cadherin degradation 5. In pancreatic cancer, the p53/FBXL20 axis suppresses PR55α stability, with reduced FBXL20 expression correlating with poor survival 4. FBXL20 has also been identified as a novel susceptibility gene for pancreatic adenocarcinoma 6 and a hub gene in obesity-related metabolic dysfunction 7.