SPOPL (speckle type BTB/POZ protein like) is a substrate adaptor for cullin-3-based E3 ubiquitin-protein ligase complexes that regulates protein degradation through the proteasome 1. As a component of the BCR (BTB-CUL3-RBX1) complex, SPOPL mediates ubiquitination of target proteins, though with lower efficiency than its paralog SPOP 1. SPOPL and SPOP can form heterodimers that act as a molecular rheostat to fine-tune E3 ligase activity 1. Mechanistically, SPOPL functions in endocytic trafficking by targeting the adaptor protein EPS15 for ubiquitin-dependent degradation at endosomes, regulating multivesicular body formation and influenza A virus entry 2. In cancer biology, SPOPL shows elevated expression in glioblastoma stem cells, where it promotes proliferation and self-renewal through Notch signaling pathway activation, associating with poor patient prognosis 3. Clinically, SPOPL copy-number loss is exclusively observed in high-risk prostate cancer patients showing exceptional response to neoadjuvant anti-androgen therapy, suggesting potential value as a predictive biomarker 4. Additionally, SPOPL has been identified as a hypermethylated oncogene in myelodysplastic syndrome, with therapeutic targeting showing promise for disease management 5.