{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:25:35Z","timestamp":1791804335237,"version":"4.3.4"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    The present investigation seeks to clarify the molecular underpinnings through which perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) precipitate recurrent miscarriage (RM). Initially, prospective targets of PFOA (6050 in total) and PFOS (8896 in total) were systematically compiled from three repositories\u2014CTD, ChEMBL, and Super-PRED\u2014while 1822 pathogenic targets linked to RM were cataloged through the amalgamation of GeneCards, OMIM, and NCBI resources. Venn diagrammatic assessment disclosed 699 overlapping targets shared between PFOA and RM, alongside 832 shared between PFOS and RM. Thereafter, PPI networks were assembled utilizing the STRING platform. By applying median filtering coupled with CytoHubba-based evaluation, central targets were distilled\u2014362 for the PFOA-RM axis and 502 for the PFOS-RM axis\u2014together with their respective top 10 hub genes. Functional enrichment conducted via DAVID pointed toward platelet coagulation elements as potentially critical mediators in PFOA- and PFOS-triggered RM. Moreover, the distinctive enrichment of transcriptional co-regulatory complexes observed specifically for PFOS, coupled with divergent pathway involvements including adipocytokine signaling, TNF cascades, and fluid shear stress transduction between the two agents, implies compound-specific pathogenic modalities. Overlapping target scrutiny pinpointed TP53 as the exclusive pathogenic gene candidate. SMART-based verification affirmed its essential structural domains, with documented subcellular residence in cytoplasmic, nuclear, and mitochondrial compartments. TP53 engages functionally with MDM2 and MDM4 among other interactors, exhibiting pronounced expression within female reproductive tissues such as the cervix and ovary. Notably, its expression proved markedly elevated in healthy villous tissues (encompassing cytotrophoblast and chorionic cavity cells) relative to decidual counterparts. Single-cell interrogation further substantiated prominent TP53 expression within migratory extravillous trophoblasts, extravillous trophoblast populations, and endometrial vascular endothelial cells.\n                    <jats:italic>Ex vivo<\/jats:italic>\n                    investigations demonstrated that PFOA and PFOS exposure markedly suppressed HTR8\/Svneo cell proliferation while promoting programmed cell death, concomitantly attenuating TP53 protein abundance. Computational molecular docking corroborated favorable binding energetics between both perfluorinated compounds and the TP53 protein. Collectively, these observations furnish novel mechanistic perspectives on PFAS-driven RM pathogenesis, highlighting TP53 as a promising molecular marker for environmentally triggered RM. Also, this study is limited by its\n                    <jats:italic>in vitro<\/jats:italic>\n                    nature, the use of a single SV40-immortalized trophoblast cell line, and the absence of primary human trophoblast or organoid validation.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1889539","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:03:46Z","timestamp":1785305026000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Systems toxicology integration uncovers trophoblast apoptosis as a pivotal mechanism underlying PFAS-related recurrent miscarriage"],"prefix":"10.3389","volume":"14","author":[{"given":"Sisi","family":"Wu","sequence":"first","affiliation":[{"name":"Intensive Care Unit, Women and Children\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Dai","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Women and Children\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lin","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Women and Children\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunyu","family":"Hong","sequence":"additional","affiliation":[{"name":"Intensive Care Unit, Women and Children\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102845","DOI":"10.1016\/j.tranon.2026.102845","article-title":"Reading the tumour at single-cell resolution: original research in the precision therapeutics special issue","volume":"70","author":"Asim","year":"2026","journal-title":"Transl. 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