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However, it remains unclear whether decidual macrophages, as key immune regulators at the maternal\u2013fetal interface, participate in the regulation of ferroptosis in trophoblast cells. This study observed significant ferroptosis in the placental trophoblast cells of patients with RSA and aborted mice. Transcriptomic sequencing results revealed that decidual macrophages derived from patients with RSA significantly promoted trophoblast cell ferroptosis while simultaneously impairing trophoblast cell function. Mechanistically, silencing heme oxygenase 1 (HMOX1) in trophoblast cells effectively reversed ferroptosis and restored trophoblast cell function, which was inhibited by decidual macrophages derived from patients with RSA. Notably, decidual macrophages regulate trophoblast ferroptosis and function by secreting C\u2010X\u2010C motif chemokine ligand 2 (CXCL2). Furthermore, the nuclear factor kappa\u2010B (NF\u2010\u03baB) pathway was significantly enriched in trophoblast cells co\u2010cultured with decidual macrophages derived from patients with RSA. Further reversal experiments indicated that the CXCL2\/NF\u2010\u03baB\/HMOX1 signaling axis may be a crucial mechanism by which decidual macrophages regulate trophoblast cell ferroptosis and function in RSA. Our subsequent findings demonstrated that trophoblast cells co\u2010cultured with RSA\u2010derived decidual macrophages promoted pro\u2010inflammatory polarization in macrophages. This effect was mediated by the interleukin\u20106 (IL\u20106) deficiency\u2010inhibited janus kinase 2 (JAK2)\/signal transducer and activator of transcription 3 (STAT3) signaling axis. Finally, pharmacological analysis revealed Eriodictyol exhibits CXCL2\u2010axis\u2010associated protective effects in RSA. In conclusion, we observed that decidual macrophages in patients with RSA can induce ferroptosis in trophoblast cells, implying that targeting this mechanism may offer novel opportunities for reshaping maternal\u2010fetal tolerance.<\/jats:p>","DOI":"10.1002\/imt2.70138","type":"journal-article","created":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T08:40:02Z","timestamp":1781426402000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decidual macrophage\u2010mediated ferroptosis in trophoblasts leads to recurrent spontaneous abortion"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3885-4944","authenticated-orcid":false,"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Renmin Hospital of Wuhan University Wuhan Hubei China"},{"name":"Central Laboratory Renmin Hospital of Wuhan University Wuhan Hubei 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