DCAF16 (DDB1 and CUL4 associated factor 16) functions as a substrate recognition component of the CUL4-DDB1 E3 ubiquitin ligase complex, mediating ubiquitination and proteasome-dependent degradation of nuclear proteins 1. The protein has emerged as a particularly attractive target for targeted protein degradation strategies, with electrophilic PROTACs capable of covalently modifying DCAF16 at cysteine residues (particularly Cys58, Cys177-179, and Cys178) to promote nuclear-restricted protein degradation 123. Notably, only a modest fraction (10-40%) of DCAF16 needs to be modified to support effective protein degradation 1. DCAF16 has been identified as a 'frequent hitter' E3 ligase in targeted protein degradation screens, likely due to its ligandability, promiscuous substrate interactions, and high occupancy in Cullin-RING complexes 4. The protein supports both PROTAC and molecular glue degrader mechanisms, including template-assisted covalent modification where structural complementarity between DCAF16 and target proteins facilitates ternary complex formation 5. Clinically, DCAF16 expression is elevated in various human carcinomas (73.5% positive rate) compared to normal tissues, with higher expression associated with better tumor differentiation, suggesting potential roles in oncogenesis 6.