ZP3 is a zona pellucida glycoprotein essential for mammalian fertilization and early reproduction. As a component of the zona pellucida (ZP), an extracellular matrix surrounding oocytes, ZP3 serves dual roles as a structural protein and sperm receptor 1. ZP3 oligosaccharides bind to acrosome-intact sperm via their plasma membrane, mediating initial sperm-egg recognition and inducing the acrosome reaction—a critical exocytotic event required for sperm penetration 12. Together with ZP2, ZP3 is necessary for ZP assembly and matrix formation 1. Following fertilization, the zona undergoes structural changes that prevent polyspermy, with ZP2 cleavage triggering oligomerization and cross-linking of ZP filaments to rigidify the egg coat 3. ZP3 mutations cause oocyte maturation arrest and female infertility. Pathogenic ZP3 variants have been identified in patients with premature ovarian insufficiency (POI) and recurrent IVF/ICSI failure 456. Additionally, ZP3 functions as an immunoregulatory receptor on dendritic cells; extracellular GPX4 binding to dendritic cell ZP3 suppresses antitumor immunity via cAMP-PRKA signaling, with high ZP3 expression predicting poor cancer prognosis 7. These findings underscore ZP3's critical roles in both reproductive biology and anti-tumor immunity.