FBXW8 is a substrate-recognition component of the Cullin7-RING (CRL7) E3 ubiquitin ligase complex that mediates proteasomal degradation of multiple target proteins. The complex recognizes phosphorylated cyclin-D1 and degrades it during S phase in response to MAPK signaling, a process essential for cancer cell proliferation 1. FBXW8 also targets insulin-receptor substrate 1 (IRS1) in an mTOR-dependent manner and regulates MAP4K1, GORASP1, and—more recently identified—YTHDF1, the latter promoting immune evasion in cancer 2. In hepatocellular carcinoma, FBXW8 acts as a tumor suppressor by degrading palmitoyl-protein thioesterase 1 (PPT1), thereby suppressing epithelial-mesenchymal transition and metastasis 3. Clinically, CRL7FBXW8 hyperactivity drives NUMB degradation in breast cancer, and genetic or pharmacologic inhibition of CRL7FBXW8 rescues transformation-related phenotypes 4. At the organism level, Fbxw8 disruption in mice causes pre- and postnatal growth retardation with reduced organ size, mirroring human 3-M syndrome caused by CUL7 mutations 5. Recent evidence reveals CRL7FBXW8 also regulates glucose-dependent lipolysis by controlling ATGL ubiquitination at the Golgi, with therapeutic potential in metabolic dysfunction-associated steatotic liver disease 6. USP5 inhibition combined with anti-PD-L1 checkpoint blockade represents an emerging combination strategy targeting FBXW8-regulated pathways in cancer.