KCTD21 functions as a substrate-specific adapter of the BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, particularly HDAC1 1. As a member of the KCASH family, KCTD21 suppresses Hedgehog pathway signaling by promoting HDAC1 degradation, which keeps the transcription factor GLI1 acetylated and transcriptionally inactive 1. This mechanism is particularly relevant in medulloblastoma, where KCTD21 expression is epigenetically silenced or deleted; restoring KCTD21 expression reduces Hedgehog-dependent tumor growth 1. Beyond its canonical role, the KCTD21 antisense RNA (KCTD21-AS1) regulates non-small cell lung cancer progression through competitive inhibition of miR-519d-5p, which targets CD47 and TIPRL, thereby modulating macrophage phagocytosis and cancer cell autophagy 2. KCTD21-AS1 is also identified as a hub node in ceRNA regulatory networks associated with hypertensive nephropathy 3. Additionally, KCTD21 variants have been implicated in neurodevelopmental disorders, including autism spectrum disorder and schizophrenia 4. Recent analyses indicate KCTD21 downregulation in ovarian cancer, suggesting potential tumor-suppressive roles 5.