FBXW7 encodes the substrate recognition component of an SCF E3 ubiquitin ligase complex that mediates proteasomal degradation of multiple oncogenic proteins including cyclin E, c-MYC, c-JUN, NOTCH, and MCL1. The protein recognizes phosphorylated degrons within target substrates and facilitates their ubiquitination for degradation. Beyond cancer-related functions, FBXW7 regulates circadian gene expression through NR1D1 degradation, participates in DNA double-strand break repair via XRCC4 ubiquitination, and suppresses osteoclast differentiation. FBXW7 is one of the most frequently mutated genes in human cancers 1. Mutations occur in 6–10% of colorectal cancers and have been documented in endometrial, lung, breast, gastric, liver, pancreatic, and other solid tumors, where they promote proliferation, invasion, and drug resistance 2. In colorectal cancer specifically, FBXW7 mutations correlate with distinct clinicopathological patterns, including early-onset disease, microsatellite instability, and chemoresistance to anti-EGFR therapies 3. The protein also regulates lipogenesis through fatty acid synthase degradation; cytoplasmic FBXW7β mutations in colorectal cancer impair FASN regulation and promote tumor growth, revealing a therapeutic opportunity with orlistat combined with cetuximab 4. Recent evidence suggests FBXW7 loss in hepatocellular carcinoma may confer sensitivity to PARP inhibitor olaparib, implicating synthetic lethal approaches 5.