biostudies-literatureUnknown6(12)Ruan TZona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin-mediated cleavage. Nevertheless, our understanding of the functional significance of furin-mediated cleavage of ZP proteins in female reproduction remains limited. Here, using mouse models with disrupted furin cleavage sites in ZP1, ZP2, and ZP3, we found that loss of the furin site in ZP2 caused female infertility associated with empty follicle syndrome (EFS), manifested by the failure to retrieve oocytes after ovarian hyperstimulation. In contrast, female mice carrying cleavage-resistant variants at the furin sites of ZP1 and ZP3 exhibited defective ZP in a subset of oocytes, leading to reduced fecundity. Mechanistically, disruption of the furin cleavage site in ZP2 impairedMedComme70542https://www.ebi.ac.uk/biostudies/studies/S-EPMC12701285biostudies-literatureFurin-Mediated Cleavage of Zona Pellucida Proteins Is Essential for Oocyte Development.PMC12701285Liu MRuan TZhuo LZhao SDai SZhang XTian YWu SJiang CMa JWang XWang YShen YWang ZXu WTang XfalseFurin-Mediated Cleavage of Zona Pellucida Proteins Is Essential for Oocyte Development.Zona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin-mediated cleavage. Nevertheless, our understanding of the functional significance of furin-mediated cleavage of ZP proteins in female reproduction remains limited. Here, using mouse models with disrupted furin cleavage sites in ZP1, ZP2, and ZP3, we found that loss of the furin site in ZP2 caused female infertility associated with empty follicle syndrome (EFS), manifested by the failure to retrieve oocytes after ovarian hyperstimulation. In contrast, female mice carrying cleavage-resistant variants at the furin sites of ZP1 and ZP3 exhibited defective ZP in a subset of oocytes, leading to reduced fecundity. Mechanistically, disruption of the furin cleavage site in ZP2 impaired2025-01-01T00:00:00Z2025 Dec2026-06-06T02:52:20.09Z2026-05-24T03:13:07.676ZS-EPMC127012854139496110.1002/mco2.70542