{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T07:08:09Z","timestamp":1783840089771,"version":"3.55.0"},"reference-count":65,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MedComm"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Zona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin\u2010mediated cleavage. Nevertheless, our understanding of the functional significance of furin\u2010mediated 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\u2010resistant 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 impaired the transmembrane transport of the non\u2010cleaved ZP2 protein and subsequently reduced the levels of SNARE proteins, ultimately triggering oocyte apoptosis through activation of the p53 and PI3K signaling pathways. Collectively, we uncovered the essential role of furin\u2010mediated cleavage of ZP proteins in female fertility and provided new mechanistic insights into the pathogenesis of EFS. These findings open new avenues for investigating the contribution of posttranslational modifications to female reproduction and for developing potential therapeutic strategies to treat female infertility.<\/jats:p>","DOI":"10.1002\/mco2.70542","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T06:44:36Z","timestamp":1765608276000},"source":"Crossref","is-referenced-by-count":1,"title":["Furin\u2010Mediated Cleavage of Zona Pellucida Proteins Is Essential for Oocyte Development"],"prefix":"10.1002","volume":"6","author":[{"given":"Tiechao","family":"Ruan","sequence":"first","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"},{"name":"Department of Pediatrics West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueguang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"},{"name":"Reproduction Medical Centre West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunchuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangchai","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbo","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-1002","authenticated-orcid":false,"given":"Ying","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics\/Gynecology Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE West China Second University Hospital, Sichuan University  Chengdu China"},{"name":"NHC Key Laboratory of Chronobiology Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1530\/rep.1.00793"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.667306"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmq044"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gah009"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmx035"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76106"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.013"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-011520-105310"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.17.3847"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.7.1119"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.122.9.2903"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2025.108560"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2025.09.001"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e03-09-0653"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2023.199283"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00904-06"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi991154y"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi002275x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod66.2.407"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.01-09-0440"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deac026"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.231"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv178"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201112094"},{"issue":"1","key":"e_1_2_11_26_1","first-page":"177","article-title":"Growth, Histology, Ultrastructure and Expression of MITF and Astacin in the Pigmentation Stages of Green, White and Purple Morphs of the Sea Cucumber","volume":"49","author":"Xing L.","year":"2018","journal-title":"Apostichopus Japonicus"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0020-711X(70)90057-1"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex015"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.009068"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1159\/000487978"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.12"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2018.04.002"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1071\/RD12116"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.theriogenology.2010.04.035"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5296.90"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.15-274522"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.3.1642"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.22744"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12524"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.278358"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2015.04.002"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0118311"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.013999"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801711200"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1999.9344"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1159\/000185181"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e16-02-0132"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2009.10.011"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.12.046"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2015.945828"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-015-0091-3"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.110.084434"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod59.2.417"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-12-0050"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-4-19"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/8239258"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2006-0028"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.9.3111-3120.2002"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(16)49898-5"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.5653\/cerm.2023.05981"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13048-024-01537-7"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioaf107"},{"key":"e_1_2_11_63_1","first-page":"21","article-title":"Zona Pellucida Genes and Proteins and Human Fertility","volume":"13","author":"Litscher E. S.","year":"2020","journal-title":"Trends in Developmental Biology"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.08.022"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7262.2005.00047.x"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2015.12.009"}],"container-title":["MedComm"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mco2.70542","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mco2.70542","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mco2.70542","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T06:41:16Z","timestamp":1783838476000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mco2.70542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":65,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/mco2.70542"],"URL":"https:\/\/doi.org\/10.1002\/mco2.70542","archive":["Portico"],"relation":{},"ISSN":["2688-2663","2688-2663"],"issn-type":[{"value":"2688-2663","type":"print"},{"value":"2688-2663","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"article-number":"e70542"}}