{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T14:19:14Z","timestamp":1777299554835,"version":"3.51.4"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["no. 2023YFC2705900"],"award-info":[{"award-number":["no. 2023YFC2705900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Reproduction Devel"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy\u2010specific liver disorder characterized by elevated maternal bile acids and an increased risk of adverse fetal outcomes. Although placental dysfunction is a key contributor to ICP pathogenesis, the underlying mechanisms remain incompletely understood. Here, we combined a Sprague\u2013Dawley rat model of ICP with spatial metabolomics to delineate region\u2010specific metabolic alterations within the placenta. Multivariate analysis revealed distinct metabolic signatures between ICP and control placentas, with pronounced reprogramming in trophoblast\u2010enriched regions. Differential metabolite and pathway analyses identified significant perturbations in glycerophospholipid metabolism, pyruvate metabolism, phospholipase D signaling, and the tricarboxylic acid cycle. Notably, phosphatidic acid (PA) was broadly elevated, whereas its downstream product phosphatidylinositol 4,5\u2010bisphosphate (PIP\n                    <jats:sub>2<\/jats:sub>\n                    ) exhibited spatially restricted accumulation in trophoblasts. Mechanistically, taurocholic acid exposure in HTR\u20108\/SVneo cells induced upregulation of PIP5K1, leading to PIP\n                    <jats:sub>2<\/jats:sub>\n                    accumulation and increased trophoblast apoptosis via disruption of the Bcl\u20102\/Bax balance. Silencing of PIP5K1 restored PIP\n                    <jats:sub>2<\/jats:sub>\n                    homeostasis and attenuated apoptosis. Importantly, these molecular alterations were recapitulated in placental tissues from ICP patients, confirming activation of the PIP5K1\u2013PIP2 axis in vivo. Collectively, our findings identify a spatially resolved PA\u2013PIP5K1\u2013PIP\n                    <jats:sub>2<\/jats:sub>\n                    lipid signaling cascade that links bile acid\u2013induced metabolic stress to trophoblast apoptosis and placental dysfunction in ICP.\n                  <\/jats:p>","DOI":"10.1002\/mrd.70105","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:26:36Z","timestamp":1776853596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PIP\n                    <sub>2<\/sub>\n                    Accumulation in the Spongiotrophoblast Drives Trophoblast Apoptosis in Intrahepatic Cholestasis of Pregnancy"],"prefix":"10.1002","volume":"93","author":[{"given":"Zhou\u2010Tian","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Health Laboratory Technology, School of Public Health Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu\u2010Xing","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Health Laboratory Technology, School of Public Health Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Health Laboratory Technology, School of Public Health Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong\u2010Ying","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Health Laboratory Technology, School of Public Health Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1682-391X","authenticated-orcid":false,"given":"Hong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Health Laboratory Technology, School of Public Health Chongqing Medical University Chongqing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7870-9445","authenticated-orcid":false,"given":"Yu\u2010Bin","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Women and Children's Hospital of Chongqing Medical University Chongqing China"},{"name":"Department of Pharmacology, Academician Work Station Changsha Medical University Changsha China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0372-6"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2024.136833"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00028.2012"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(19)31270-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.03.039"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-32554-0_1"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1997.77.2.303"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2022.101771"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.2049"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2019.12.007"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-018-4850-1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo12090776"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166269"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.220334"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1522-5178"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jog.15173"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.48095\/cccg2024405"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.10.025"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101665"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioae064"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpm-2022-0570"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2013.10.019"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2019.07.006"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1213757"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(18)31877-4"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.5114\/ceji.2014.43723"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05185"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2004.10.020"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.18388\/abp.2020_5841"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk1887"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-024-02458-x"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03888-2"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000341"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.01.009"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12230"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2024.01.021"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-022-01443-4"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.122.061934"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00001.2005"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/aog.0000000000000346"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2022.2136400"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep38946"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/jog.12549"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1220323"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30774"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2019.7891"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajogmf.2023.100952"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deae091"}],"container-title":["Molecular Reproduction and Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mrd.70105","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mrd.70105","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mrd.70105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T13:30:28Z","timestamp":1777296628000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mrd.70105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/mrd.70105"],"URL":"https:\/\/doi.org\/10.1002\/mrd.70105","archive":["Portico"],"relation":{},"ISSN":["1040-452X","1098-2795"],"issn-type":[{"value":"1040-452X","type":"print"},{"value":"1098-2795","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2025-11-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70105"}}