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Here, we report elevated circulating pro\u2010apoptotic proteins in EOPE patients at early pregnancy, along with concurrent CASP3 activation and GSDME cleavage in EOPE placentas. Using multiple trophoblast cell lines, we demonstrate that trophoblast cells, which highly express GSDME, undergo a shift from apoptosis to CASP3\u2010dependent pyroptosis, driving inflammation. Notably, pyroptotic trophoblasts further induce pro\u2010inflammatory macrophage polarization within placental villi organoids, establishing a feedback loop that amplifies both trophoblast pyroptosis and inflammatory responses in trophoblast organoids\u2010macrophage assembloids. In vivo, CASP3\u2010GSDME\u2010mediated trophoblast pyroptosis contributes to systemic inflammation in wild\u2010type pregnant mice but not in\n                    <jats:italic>\n                      Gsdme\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Screening of EOPE prevention drugs reveals Vitamin D as a suppressor of GSDME activation and pyroptosis in trophoblast cells. Together, our findings establish CASP3\u2013GSDME\u2013mediated pyroptosis as a mechanistic link between apoptosis and inflammation in EOPE.\n                  <\/jats:p>","DOI":"10.1002\/advs.202516948","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:49:23Z","timestamp":1768978163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Caspase\u20103\/GSDME\u2010Mediated Trophoblast Pyroptosis and Reciprocal Macrophage Polarization Contribute to Inflammation in Early\u2010Onset Preeclampsia"],"prefix":"10.1002","volume":"13","author":[{"given":"Baoying","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center For Obstetrics and Gynecology Guangdong\u2010Hong Kong\u2010Macao Greater Bay Area Higher Education Joint Laboratory of 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