{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:09:02Z","timestamp":1788952142114,"version":"build-2803163510"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Preeclampsia (PE) is characterized by placental hypoxia, metabolic stress, trophoblast dysfunction, and impaired spiral artery remodeling, but the mechanisms linking these abnormalities remain incompletely understood. Cuproptosis, a recently identified form of regulated cell death driven by copper-dependent aggregation of lipoylated tricarboxylic acid cycle proteins, may provide a mechanistic link between placental metabolic stress and trophoblast injury. Here, we propose a hypothesis in which hypoxia-induced glycolytic reprogramming and lactate accumulation promote histone H3K18 lactylation, activate GRHL2, and increase SLC31A1\/CTR1-mediated copper uptake. Subsequent FDX1-dependent copper reduction, DLAT aggregation, Fe-S cluster loss, and mitochondrial proteotoxic stress may preferentially affect mitochondria-rich villous syncytiotrophoblasts, while also impairing EVT function. Cuproptosis may interact with ferroptosis and oxidative stress through shared metal-redox and mitochondrial vulnerabilities. Although current evidence does not establish cuproptosis as an initiating cause of PE, it may amplify placental dysfunction. Targeting copper transport, mitochondrial stress, or pathway-specific biomarkers warrants further investigation.<\/jats:p>","DOI":"10.3389\/fendo.2026.1926486","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:12:21Z","timestamp":1788948741000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cuproptosis: a novel mechanism linking placental metabolic stress to trophoblast injury in preeclampsia"],"prefix":"10.3389","volume":"17","author":[{"given":"Ling","family":"Liu","sequence":"first","affiliation":[{"name":"The Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoxiang","family":"Xing","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Affiliated Hospital of Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jogoh.2020.101975","article-title":"Preeclampsia: pathophysiology and management","volume":"50","author":"Nirupama","year":"2021","journal-title":"J Gynecology Obstetrics Hum Reprod"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-021-02660-y","article-title":"Maternal serum levels of zinc, copper, and thiols in preeclampsia patients: 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