MAEA (macrophage erythroblast attacher) is a core catalytic component of the CTLH E3 ubiquitin ligase complex that mediates K48-linked polyubiquitination and proteasomal degradation of multiple substrates. Beyond its classical role in erythroblast-macrophage interactions and erythrocyte maturation, recent evidence reveals MAEA as a critical regulator of genome stability and cancer progression. MAEA facilitates homologous recombination DNA repair by mediating Ku80 ubiquitination and removal from replication forks, enabling RAD51 loading and protecting against replication stress 12. In cancer contexts, MAEA promotes glioblastoma progression through PHD3 degradation and HIF-1α stabilization 3, while conversely suppressing gastrointestinal cancer through PARP1 degradation and enhanced macrophage phagocytosis 4. MAEA also negatively regulates mTORC1 signaling via ZMYND19 and MKLN1 degradation 5 and restricts intracellular bacterial growth by modulating host autophagy and metabolic responses 6. Pathogenic MAEA variants cause a neurodevelopmental disorder (DIADEM) characterized by microcephaly and developmental delay due to impaired DNA repair capacity 12.