KLHL21 (kelch-like family member 21) is a substrate-specific adapter of the Cul3-based E3 ubiquitin ligase complex (BCR(KLHL21)) that regulates multiple cellular processes. Functionally, KLHL21 is required for efficient chromosome 1 and cytokinesis by controlling translocation of the chr1 passenger complex (CPC) from chr1 to the spindle midzone during anaphase 1. The complex mediates ubiquitination of aurora B kinase (AURKB), though this modification may not lead to proteasomal degradation 1. Clinically, KLHL21 exhibits tumor-suppressive functions across multiple cancer types. In gastric cancer, KLHL21 loss promotes STAT3 activation through PABPC1-mediated PIK3CB translational enhancement, driving metaplasia-to-dysplasia progression and poor survival outcomes 2. In hepatocellular carcinoma, KLHL21 upregulation correlates with cancer progression and serves as a potential therapeutic target 3. Conversely, in breast cancer, KLHL21 downregulation reduces KLHL21-mediated IKKβ binding, allowing NF-κB p65 pathway activation and promoting metastasis 4. Similarly, in cholangiocarcinoma and bladder cancer, KLHL21 inhibition accelerates proliferation via ERK pathway activation and NF-κB signaling respectively 5, 6. Recently, KLHL21 was identified among prognostic gene signatures for hepatocellular carcinoma 7 and in ubiquitination-related diagnostic signatures for Alzheimer's disease 8, suggesting broader pathological relevance beyond cancer.