ZPBP (zona pellucida binding protein) is a type 2 transmembrane protein with an extracellular zona pellucida binding homologous (ZPBH) domain containing 15 conserved cysteine residues 1. Primary Function: ZPBP plays critical roles in sperm-oocyte interaction during fertilization, specifically mediating sperm binding to the zona pellucida (ZP). Mechanism: ZPBP functions as part of the zona pellucida block to polyspermy (ZPBP), which prevents multiple sperm from fertilizing a single oocyte 2. The protein localizes to the sperm acrosome and forms complexes with other acrosomal proteins like ACTL7A, contributing to proper acrosome morphogenesis and maintaining correct sperm-ZP binding capacity 3. Defects in ZPBP maturation, regulated by CALR3, compromise sperm-ZP binding and cause fertilization failure 4. Disease Relevance: ZPBP mutations are associated with spermatogenic failure 66 and male infertility characterized by failed sperm-zona pellucida interaction. Altered ZPBP localization or expression impairs fertilization success in vitro and in vivo 3. ZPBP downregulation occurs in obesity-associated male infertility 5 and in acrosomal defects caused by FSIP2 mutations 6. Clinical Significance: ZPBP defects represent a specific cause of male factor infertility amenable to intracytoplasmic sperm injection (ICSI), which bypasses the requirement for normal sperm-ZP binding 4.