FBXL12 (F-box and leucine rich repeat protein 12) is a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes that mediates polyubiquitination and proteasomal degradation of multiple target proteins. Originally characterized for its role in cell cycle regulation through CAMK1 degradation and G1 arrest in lung epithelia, FBXL12 has broader functions in genomic stability and disease processes. In DNA repair, FBXL12 regulates the Fanconi anemia pathway by promoting FANCD2 degradation at stalled replication forks following CHK1-dependent phosphorylation, facilitating replication recovery under replication stress 1. FBXL12 also participates in DNA double-strand break repair through neddylation-dependent removal of KU70/KU80 from DNA ends, preventing excessive Ku chr19 accumulation that would impair transcription 2. During T cell development, Notch and pre-TCR signaling cooperatively induce FBXL12 expression to degrade Cdkn1b, promoting β-selected thymocyte proliferation 3. In disease contexts, FBXL12 upregulation correlates with reduced survival in high CYCLIN E-expressing breast tumors, identifying it as a vulnerability in replication stress-dependent cancers 1. In pancreatic cancer, disrupting sorcin-PAX5 interactions promotes PAX5-mediated FBXL12 expression, leading to ALDH1A1 ubiquitination and ferroptosis induction 4. Additionally, FBXL12 expression in activated microglia promotes scarless spinal cord injury repair through MYH14 ubiquitination and cytoskeletal reorganization, reducing scar formation by ~70% and restoring motor function 5. Genome-wide association studies identify FBXL12 as associated with sleep duration variation 6.