FBXW5 (F-box and WD repeat domain containing 5) is a substrate recognition component of SCF and DCX E3 ubiquitin ligase complexes that regulates protein degradation through the ubiquitin-proteasome system 1. The protein functions as a key regulator of multiple cellular processes by targeting specific substrates for ubiquitination and proteasomal degradation. FBXW5 controls autophagy through the ULK1-FBXW5-SEC23B axis, where it targets SEC23B (a COPII component) for degradation under nutrient-rich conditions, while ULK1 phosphorylation of SEC23B during starvation prevents this degradation, enabling autophagosome biogenesis 2. The protein also regulates ciliogenesis by targeting kinesin-13 family members (MCAK, Kif2a, Kif2b) for degradation during G2 phase, with loss of FBXW5 impairing ciliogenesis 3. In disease contexts, FBXW5 shows tissue-specific effects: in hepatocellular carcinoma, it targets AQP3 for degradation, suppressing autophagic cell death via the PDPK1-AKT-MTOR pathway 4, while in breast cancer, it promotes progression by enhancing KLF13 ubiquitination and activating PI3K/AKT signaling 5. FBXW5 also correlates with insulin sensitivity in skeletal muscle 6 and aggravates hepatic ischemia/reperfusion injury through ASK1 activation 7, highlighting its therapeutic potential across multiple pathological conditions.