KCTD5 (potassium channel tetramerization domain containing 5) functions as a substrate adapter for the Cullin3-RING E3 ubiquitin ligase complex, modulating protein stability through selective ubiquitination rather than degradation. It interacts with diverse substrates including ΔNp63α, Ikaros, and β-catenin, regulating their monoubiquitination and post-translational modification 1. Beyond ubiquitin-dependent pathways, KCTD5 serves as a positive regulator of TRPM4 calcium-activated cationic channels and acts as a major regulator of neuronal cAMP signaling through zinc influx modulation 2, 3. KCTD5 also functions in cell migration by modulating focal adhesion dynamics and cellular spreading through Rac1 activity and calcium signaling 4. Functionally redundant with KCTD2 and KCTD17, these proteins regulate cellular growth and proliferation through effects on G protein subunit expression 5. In disease contexts, KCTD5 has emerged as a cancer-associated factor: it stabilizes β-catenin in colorectal cancer cells through complement-mediated signaling 6, mediates chemotherapy-induced Ikaros degradation in hematological cells 7, and confers tyrosine kinase inhibitor resistance in chr16 myeloid leukemia by promoting BCR::ABL1 ubiquitination 8. Pan-cancer studies identify KCTD5 as a prognostic biomarker associated with apoptosis regulation and chemotherapy sensitivity 9.