ZP4 (zona pellucida glycoprotein 4) encodes a critical structural component of the zona pellucida, the extracellular matrix surrounding mammalian oocytes and early embryos 1. ZP4 functions as part of a complex filamentous network composed of ZP1, ZP2, ZP3, and ZP4 that forms left-handed double helical structures essential for egg coat integrity 2. The protein serves multiple roles in reproduction: it acts as a sperm receptor that binds to capacitated human spermatozoa and induces dose-dependent acrosome reactions necessary for fertilization 1. ZP4 interacts with various sperm head proteins through complex recognition mechanisms involving moonlighting proteins such as glycolytic enzymes and structural proteins 3. Functionally, ZP4 is essential for conferring structural properties to the zona pellucida that protect developing embryos. ZP4-deficient rabbit models demonstrate that loss of this protein results in significantly thinner, more permeable zona pellucida with disorganized, fenestrated architecture, severely impairing embryo development and fertility despite normal ovulation and fertilization 4. Clinically, ZP4 mutations have been identified in patients with abnormal zona pellucida morphology, and reduced ZP4 expression is observed in certain polycystic ovary syndrome phenotypes 56. Additionally, ZP4 shows promise as a therapeutic target, being investigated for CAR-T cell therapy in triple-negative breast cancer due to its restricted expression pattern 7.