FBXO10 (F-box protein 10) is a substrate-recognition component of the SCF-type E3 ubiquitin ligase complex that mediates ubiquitination and proteasomal degradation of key cellular proteins. Primary substrates include BCL2 (an antiapoptotic protein), RAGE, HGAL/GCSAM, ACSL4, and PGAM5, through which FBXO10 regulates apoptosis, ferroptosis, and mitochondrial proteostasis 1234. Mechanistically, FBXO10 catalyzes K48-linked ubiquitination of ACSL4, a critical lipid-metabolizing enzyme 5. This ubiquitination-driven degradation suppresses ferroptosis by reducing arachidonic acid-phospholipid biosynthesis 12. Additionally, FBXO10 localizes to the outer mitochondrial membrane via geranylgeranylation at cysteine 953, where it controls PGAM5 stability to maintain mitochondrial homeostasis 4. Disease relevance is substantial: rare FBXO10 missense variants increase mosaic X chromosome 9 risk, a precursor to hematologic malignancies 6. In colorectal and esophageal cancers, elevated FBXO10 promotes tumor progression and immunotherapy resistance by suppressing ferroptosis 23. However, in ovarian cancer, deleterious FBXO10 variants associate with reduced disease risk 7. Stress-responsive FBXO10 upregulation, mediated by LEDGF binding, may contribute to breast cancer susceptibility 8.