DCAF1 (DDB1 and CUL4 associated factor 1) is a multifunctional substrate adaptor for CUL4-based E3 ubiquitin ligase complexes that regulates protein degradation and cellular homeostasis. Its WD40 domain serves as a substrate recruitment module, enabling ubiquitination and proteasomal degradation of diverse substrates 1. DCAF1 functions as a histone H2AT120 kinase and phosphorylates non-histone proteins like EZH2, driving epigenetic gene silencing in colon cancer cells 2. Additionally, DCAF1 mediates ubiquitin-dependent degradation of Nrf2, with miR-3175-mediated DCAF1 silencing activating Nrf2 signaling to protect osteoblasts from dexamethasone-induced oxidative stress 3. Clinically, DCAF1 is overexpressed in multiple cancers. In hepatocellular carcinoma, DCAF1 activates Akt signaling via PARD3 interaction to promote proliferation and metastasis 4. Under glucose deprivation, DCAF1-mediated Rheb degradation inhibits mTORC1 and promotes cancer cell survival 5. DCAF1 also regulates HIV replication through multiple mechanisms: HIV-2 Vpr hijacks DCAF1 to enhance macrophage infection 6, while DOT1L-recruited DCAF1 restricts HIV-1 reactivation by ubiquitinating NF-κB 7. DCAF1's diverse substrate specificity makes it a promising therapeutic target for cancer and HIV treatment through PROTACs and small molecule inhibitors 8.