FBXO43 is an F-box protein with dual roles in reproductive and oncogenic contexts. In gametogenesis, FBXO43 functions as a critical negative regulator of the anaphase-promoting complex/cyclosome (APC/C) 1, establishing and maintaining oocyte arrest at metaphase II until fertilization. Loss-of-function mutations in FBXO43 cause non-obstructive azoospermia through meiotic arrest in spermatocytes 1 and amorphous sperm head defects 2, while mutations also impede oocyte maturation 3. FBXO43 accomplishes these functions by recognizing phosphorylated proteins and promoting their ubiquitination and degradation, particularly modulating CCNB1 and CDK1 during meiosis. Conversely, FBXO43 exhibits oncogenic activity in somatic tissues. In cancer cells, FBXO43 is overexpressed and promotes cell cycle progression by stabilizing SKP2 through reduced auto-ubiquitylation 4. This function correlates with enhanced proliferation, migration, and invasion in breast cancer and hepatocellular carcinoma 567. High FBXO43 expression predicts unfavorable prognosis and associates with advanced tumor stage and immunosuppression 67. Thus, FBXO43 represents a potential therapeutic target for cancer treatment while explaining infertility phenotypes through loss-of-function mutations.