FBXO39 (F-box protein 39) functions as a substrate-recognition component of SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes, facilitating targeted protein degradation through the ubiquitin-proteasome system 1. The protein plays crucial roles in cellular proliferation and apoptosis regulation, as demonstrated by knockdown studies showing reduced cell proliferation and increased apoptosis in osteosarcoma cells 1. FBXO39 exhibits cancer-testis antigen properties, with restricted expression in normal testicular tissue but aberrant overexpression in various malignancies 23. Mechanistically, FBXO39 maintains mitochondrial homeostasis by targeting lysine-specific demethylase 5A (KDM5A) for ubiquitination-dependent degradation, which regulates H3K4me3 demethylation at the SSBP1 promoter and prevents mitochondrial dysfunction and ferroptosis 4. Clinically, FBXO39 overexpression correlates with poor prognosis across multiple cancer types including glioblastoma, colon cancer, and breast cancer 5236. In gliomas, high FBXO39 expression associates with increased tumor grade, enhanced invasion/migration capabilities, and stem cell characteristics 5. Its diagnostic and prognostic potential, combined with its cancer-restricted expression pattern, makes FBXO39 an attractive biomarker and potential immunotherapy target 76.