FBXO46 is an F-box protein component of the SCF(FBXO46) ubiquitin ligase complex that functions as a substrate-recognition adaptor for protein degradation 1. In unstressed cells, FBXO46 recognizes RXXR motifs on FBXO31 to promote its polyubiquitination and proteasomal degradation, maintaining basal FBXO31 levels and preventing premature senescence 1. FBXO46 also negatively regulates p53 tumor suppressor activity by directly binding to and stabilizing Mdm2, its principal E3 ubiquitin ligase, thereby enhancing p53 degradation and promoting cell proliferation and G1/S cell cycle progression 2. Following genotoxic stress, ATM-mediated phosphorylation of FBXO46 triggers its degradation, allowing FBXO31 accumulation and genomic stability maintenance 1. Clinically, elevated FBXO46 expression associates with poor outcomes in colorectal cancer as part of a prognostic 4-gene signature (HR: 3.42, p<0.001) 3, and represents a potential therapeutic target in triple-negative breast cancer linked to USP2-mediated signaling 4. FBXO46 variants also show suggestive association with mitral valve prolapse risk 5.