KCTD5 (potassium channel tetramerization domain containing 5) functions primarily as a substrate adapter for cullin3-based E3 ubiquitin ligase complexes 1. The protein does not modulate canonical voltage-gated potassium channels 2, but instead regulates diverse cellular processes through protein modifications and interactions. Mechanistically, KCTD5 operates within CRL3 complexes to mediate polyubiquitination and monoubiquitination of multiple substrates. It induces K63-linked polyubiquitination of β-catenin in the complement C5a/C5aR1 pathway, enhancing β-catenin stability and Wnt signaling 3. KCTD5 also monoubiquitinates ΔNp63α, impairing its DNA-binding activity 4, and stabilizes Ikaros protein while mediating its degradation in response to chemotherapy 5. Additionally, KCTD5 regulates BCR::ABL1 ubiquitination in chr16 myeloid leukemia 6 and controls cAMP signaling through zinc-dependent allosteric modulation of adenylyl cyclases 7. Clinically, KCTD5 expression correlates with cancer prognosis, immune microenvironment composition, and chemotherapy sensitivity across multiple cancer types 8. Functionally redundant KCTD family members collectively maintain cellular proliferation and survival 9. These diverse roles position KCTD5 as a critical regulator of cell signaling and protein homeostasis with significant implications for cancer biology and therapeutic resistance.