WDR20 (WD repeat domain 20) is a regulatory cofactor that activates deubiquitinating enzyme complexes, primarily functioning as a catalytic modulator of USP12 and USP46 deubiquitinases 12. Structurally, WDR20 anchors at the base of the ubiquitin-contacting loop of USP12 and remotely modulates its catalytic center 2. WDR20 regulates subcellular shuttling of the USP12/UAF1/WDR20 complex between the plasma membrane, cytoplasm, and nucleus via CRM1-dependent nuclear export pathways 3. Mechanistically, WDR20-containing complexes control protein stability through selective deubiquitination. The USP12/46-WDR20 complex stabilizes β1 integrin by removing ubiquitin chains in early endosomes, preventing ESCRT-mediated lysosomal degradation 4. Similarly, the USP46-WDR20 complex promotes Wnt/β-catenin signaling by deubiquitinating the LRP6 coreceptor 5. In hepatocellular carcinoma, WDR20 orchestrates USP12/46-mediated deubiquitination of c-Myc, promoting HCC cell proliferation and preventing senescence 6. Clinical significance includes prostate cancer progression, where elevated WDR20 expression supports androgen receptor stability and activity 7. WDR20 also regulates ERAD substrate degradation through interactions with p97 and E3 ligases 8. Recent evidence links WDR20 to epilepsy pathogenesis through USP46-mediated AMPA receptor deubiquitination 9. WDR20 represents a therapeutic target across multiple cancer types and neurological conditions.