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Asperosaponin VI (AVI), a major active triterpene saponin extracted from Dipsacus asperoides, has emerged as a promising therapeutic candidate for SA; however, its precise molecular mechanisms remain poorly elucidated. This study aimed to investigate the protective efficacy of AVI against SA and clarify its underlying pathways. In vivo, an SA model was established via the subcutaneous administration of bromocriptine. AVI intervention significantly reduced the embryo resorption rate and ameliorated placental injury. Biochemically, AVI attenuated the accumulation of MDA and Fe2+, downregulated pro-ferroptotic markers (TFR-1 and ACSL4), and systematically modulated the expression of SLC7A11 alongside the ferroptosis-related KEAP1\/NRF2\/GPX4 signaling axis. In silico analyses, including molecular docking and molecular dynamics simulations, confirmed a robust binding affinity between AVI and NRF2. In vitro, AVI dose-dependently reversed erastin-induced trophoblast dysfunction and mitochondrial impairment, while effectively abrogating the ferroptosis-associated overproduction of ROS, Fe2+, and MDA. Crucially, pharmacological inhibition of NRF2 by ML385 partially negated these cytoprotective effects. Comprehensive molecular analyses (RT-qPCR, IF and Western blotting) revealed that AVI suppressed KEAP1 while concomitantly upregulating NRF2, GPX4, and SLC7A11. In conclusion, AVI prevents SA by suppressing trophoblast ferroptosis through KEAP1\/NRF2\/GPX4 signaling, offering a novel therapeutic approach.<\/jats:p>","DOI":"10.3390\/antiox15060699","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:33:14Z","timestamp":1780479194000},"page":"699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Asperosaponin VI Ameliorates Spontaneous Abortion by Inhibiting Trophoblast Ferroptosis via the KEAP1\/NRF2\/GPX4 Axis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7448-655X","authenticated-orcid":false,"given":"Yangyang","family":"Duan","sequence":"first","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9909-4118","authenticated-orcid":false,"given":"Xinyu","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahong","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianglun","family":"Ji","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4312-8995","authenticated-orcid":false,"given":"Jinghang","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8288-8609","authenticated-orcid":false,"given":"Zhangrui","family":"Nie","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairuo","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxi","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0578-370X","authenticated-orcid":false,"given":"Yuhan","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1320-8083","authenticated-orcid":false,"given":"Zhonglin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8016-9838","authenticated-orcid":false,"given":"Fan","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5744","DOI":"10.1038\/s41467-024-49993-5","article-title":"Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss","volume":"15","author":"Sonehara","year":"2024","journal-title":"Nat. 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