WDR48 (WD repeat domain 48) is a critical regulator of deubiquitinating enzymes that plays essential roles in DNA damage response and cellular homeostasis. The protein functions as an activator of multiple ubiquitin-specific proteases, including USP1, USP12, and USP46, forming ternary complexes that regulate protein stability and cellular processes 1 2. WDR48 interacts with USP46 through a highly polar surface on its β-propeller structure, stabilizing substrate binding and prolonging residence time to enhance deubiquitinase activity 1. In DNA damage response, WDR48 works with USP1 to prevent PCNA degradation in DNA repair-deficient cells, representing a synthetic lethal interaction 3. The protein also protects integrins from lysosomal degradation by forming a USP12/46-WDR48-WDR20 complex that removes ubiquitin from internalized β1 integrin 2. In hepatocellular carcinoma, WDR48 promotes tumor progression by stabilizing c-Myc through deubiquitination, enhancing cell proliferation and EMT signaling 4. Additionally, WDR48 modulates SLFN11 activation during replication stress, contributing to cellular responses to DNA damage 5. The USP1/WDR48 complex has emerged as a potential therapeutic target in cancer stem cell regulation 6.