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Ferroptosis has recently emerged as a key contributor to placental pathology; however, the upstream regulatory mechanisms that activate ferroptosis in trophoblasts remain incompletely defined. Circular RNAs (circRNAs) have been implicated in trophoblast dysfunction, yet the ferroptosis\u2010related circRNA network in PE is largely unexplored. This study investigated whether circCOL3A1 regulates p53\u2010mediated ferroptosis in trophoblasts and contributes to PE pathogenesis. CircCOL3A1 expression was examined in placental tissues and HTR\u20108\/SVneo cells. Hypoxia and hypoxia\/reoxygenation models were used to mimic PE\u2010associated stress in\u00a0vitro. Loss\u2010 and gain\u2010of\u2010function assays, ferroptosis measurements, RNA pull\u2010down, RIP, FISH, and Actinomycin\u2010D stability analyses were performed to elucidate the circCOL3A1\/TIAL1\/p53 axis. A reduced uterine perfusion pressure (RUPP) rat model was used to evaluate the in\u00a0vivo effects of circCOL3A1 knockdown. CircCOL3A1 was significantly elevated in PE placentas and hypoxia\u2010treated trophoblasts, exhibiting cytoplasmic localization and high structural stability. CircCOL3A1 knockdown restored trophoblast migration, invasion, viability, and reduced apoptosis under hypoxia. Silencing circCOL3A1 suppressed hypoxia\u2010induced ferroptosis by reducing ROS, MDA, and iron levels while restoring GSH and GPX4. Mechanistically, circCOL3A1 bound the RNA\u2010binding protein TIAL1 to enhance p53 mRNA stability, thereby promoting p53\u2010dependent ferroptosis. In\u00a0vivo, circCOL3A1 silencing lowered maternal blood pressure and proteinuria, reduced placental ferroptosis, and improved fetal survival in PE rats. CircCOL3A1 drives trophoblast ferroptosis through a TIAL1\u2010dependent stabilization of p53, contributing to PE progression. Targeting the circCOL3A1\/TIAL1\/p53 axis may offer a promising therapeutic strategy for preeclampsia.<\/jats:p>","DOI":"10.1096\/fj.202601128r","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T13:45:27Z","timestamp":1781531127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>CircCOL3A1<\/scp>\n                    Drives Trophoblast Ferroptosis Through\n                    <scp>TIAL1<\/scp>\n                    \u2010p53 Axis to Promote Preeclampsia Progression"],"prefix":"10.1096","volume":"40","author":[{"given":"Haidong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Obstetrics The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University  Huai'an Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhong","family":"Yin","sequence":"additional","affiliation":[{"name":"Changzhou Key Laboratory of Maternal and Child Health Medicine  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University  Huai'an Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9088-7751","authenticated-orcid":false,"given":"Zhonghua","family":"Shi","sequence":"additional","affiliation":[{"name":"Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center Nanjing Medical University  Changzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Women\u2019s Hospital of Nanjing Medical University, Nanjing Women and Children\u2019s Healthcare Hospital  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313276"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000003891"},{"issue":"4","key":"e_1_2_13_4_1","article-title":"Preeclampsia\u2014A Disease of Pregnant Women","volume":"64","author":"Filipek A.","year":"2018","journal-title":"Postepy Biochemii"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioaf151"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1017\/S204017441900014X"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2016.09.007"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252212195"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856-024-00642-4"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1891\/NN-2024-0001"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03104-6"},{"issue":"1","key":"e_1_2_13_12_1","article-title":"Ferroptosis: Mechanisms and Links With Diseases. 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