FBXL2 (F-box and leucine rich repeat protein 2) functions as a substrate recognition component of the SCF(FBXL2) E3 ubiquitin ligase complex, mediating polyubiquitination and proteasomal degradation of target proteins 1. Unlike typical F-box proteins, FBXL2 recognizes calmodulin-binding motifs rather than phosphodegrons, and calmodulin antagonizes its activity 1. FBXL2 targets diverse substrates including cyclins CCND2/CCND3 (inducing G0 cell-cycle arrest) 1, PIK3R2 (regulating PI3K signaling and autophagy) 2, and NLRP3 (negatively regulating inflammasome assembly) 3. Membrane localization of FBXL2 is mediated by GGTase-3-catalyzed geranylgeranylation, enabling degradation of membrane-anchored proteins 4. Clinically, FBXL2 functions as a tumor suppressor: it inhibits breast cancer stemness and paclitaxel resistance by targeting transcription factor E47 5, suppresses gastric cancer proliferation via FoxM1 degradation 6, and sensitizes HER2-negative breast cancers to trastuzumab deruxtecan by promoting HER2 degradation 7. In cardiac tissue, FBXL2 preserves mitochondrial integrity and function through FUNDC1-mediated IP3R3 degradation 8. Post-translational modifications, including O-GlcNAcylation, regulate FBXL2 stability and activity, influencing cancer progression 9.