FBXO21 is a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes that mediates the polyubiquitination and proteasomal degradation of multiple protein targets. The protein recruits SKP1, CUL1, and RBX1 to form functional ubiquitin ligase machinery and recognizes diverse substrates including p85α (a regulatory subunit of PI3K), EID1, KRT16, NMNAT2, and ASK1 12345. FBXO21 expression is frequently reduced in cancer tissues and inversely correlates with disease progression. In acute myeloid leukemia, FBXO21 silencing promotes differentiation and sensitizes cells to chemotherapy through degradation of p85α and suppression of PI3K signaling 1. In clear cell renal cell carcinoma, FBXO21 overexpression inhibits proliferation and metastasis via the CREB pathway and immune cell infiltration 6. In lung cancer, FBXO21-mediated KRT16 degradation suppresses metastasis; notably, IL-15 upregulates FBXO21 and is elevated in nonmetastatic patients 3. FBXO21 also regulates axon survival after nerve injury by controlling NMNAT2 stability; Fbxo21 knockout mice show prolonged injured nerve survival 4. In degenerative diseases, FBXO21 elevation promotes osteoarthritis and intervertebral disc degeneration through ERK pathway activation and autophagy inhibition 78. These findings position FBXO21 as a key regulator of cancer progression and neurodegeneration with potential therapeutic relevance.