DCAF7 (DDB1 and CUL4 associated factor 7) functions as a substrate receptor for the CUL4-DDB1 E3 ubiquitin ligase complex, mediating the degradation of multiple protein substrates. Beyond its canonical role in ubiquitin-dependent proteolysis, DCAF7 acts as a scaffold protein facilitating protein-protein interactions between deubiquitinases and their substrates. 1 In DNA replication, DCAF7 targets DNA ligase I for ubiquitylation and degradation, regulating the stoichiometry of DNA replication proteins. 2 Clinically, DCAF7 has emerged as a significant oncogenic driver across multiple cancer types. In nasopharyngeal carcinoma, DCAF7 mediates chemoresistance to docetaxel-cisplatin-5-fluorouracil therapy by recruiting USP10 to deubiquitylate G3BP1, promoting stress granule formation and metastasis. 1 In pancreatic neuroendocrine tumors, the CUL4B-DCAF7 axis promotes MEN1 tumor suppressor degradation, and DCAF7 downregulation overcomes everolimus resistance. 3 In hepatocellular carcinoma, DCAF7 stabilizes β-catenin to activate Wnt signaling, driving proliferation and migration while simultaneously promoting immune evasion through checkpoint gene upregulation. 4 Additionally, DCAF7 recruits USP2 to suppress clockophagy-induced ferroptosis in HCC. 5 Defensively, DCAF7 functions as a host antiviral factor, restricting influenza A virus replication by promoting degradation of the viral PA polymerase subunit. 6 DCAF7 also participates in mTORC1 sensing of mitochondrial dysfunction. 7 DCAF7 is considered a candidate gene for neurodevelopmental disorders. 8