FBXO21 is an F-box protein that functions as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, mediating polyubiquitination and proteasomal degradation of multiple cellular substrates. 1 FBXO21 recruits SKP1, CUL1, and RBX1 to form the SCFFBXO21 complex, which targets diverse proteins for degradation including p85α (regulatory subunit of PI3K), 2 NMNAT2 (axonal survival protein), 3 EID1 (transcriptional repressor), 1 and KRT16 (metastasis-associated keratin). 4 In acute myeloid leukemia (AML), FBXO21 exhibits low expression correlating with poor prognosis, and its knockdown leads to differentiation and chemotherapy sensitization through p85α degradation and reduced PI3K signaling. 2 Conversely, in clear cell renal cell carcinoma and lung cancer, FBXO21 functions as a tumor suppressor, with overexpression inhibiting proliferation and metastasis. 5 4 FBXO21 expression is epigenetically regulated through DNA methylation. 5 FBXO21 also plays critical roles in degenerative diseases. In intervertebral disc degeneration and osteoarthritis, FBXO21 is upregulated and promotes pathology by inhibiting autophagy through ERK pathway activation, suppressing cartilage anabolism and promoting catabolism. 6 7 In contrast, in nerve injury, FBXO21 promotes axon degeneration by degrading NMNAT2, and its knockout provides axonal protection. 3 These findings establish FBXO21 as a multifunctional E3 ligase with context-dependent roles in oncology and neurodegeneration.