USP46 (ubiquitin specific peptidase 46) is a deubiquitinating enzyme that requires WDR48 and WDR20 cofactors for optimal catalytic activity 1. The enzyme plays crucial roles in multiple cellular processes through substrate-specific deubiquitination. In Wnt signaling, USP46 forms a complex that deubiquitylates the Wnt coreceptor LRP6, promoting its stability and facilitating Wnt/β-catenin pathway activation essential for intestinal organoid viability 1. USP46 regulates synaptic transmission by controlling AMPA receptor trafficking, where DEPDC5/mTORC1 signaling modulates USP46 levels to maintain excitatory/inhibitory balance 2. The enzyme also deubiquitinates integrins, protecting them from lysosomal degradation and maintaining surface receptor levels 3. USP46 exhibits oncogenic properties in multiple cancers: it stabilizes oncogenic NRAS mutants when activated by CK1δ phosphorylation in melanoma 4, promotes HPV-transformed cancer proliferation by stabilizing Cdt2 5, and enhances triple-negative breast cancer progression through PGAM1 stabilization and glycolysis regulation 6. Additionally, USP46 functions as a histone H2A/H2B deubiquitinase regulating gene expression during development 7 and protects podocytes in diabetic nephropathy by preventing TDP-43 aggregation 8.