{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T20:03:24Z","timestamp":1769803404846,"version":"3.49.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"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. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Preterm birth (PTB) remains the leading cause of neonatal mortality and long-term complications, yet its molecular mechanisms are incompletely understood. Fibroblasts, as critical components of the gestational microenvironment, have an undefined role in PTB pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study employed single-cell RNA sequencing (scRNA-seq) datasets from murine preterm birth models (GSE200289 and E-MTAB-11491), processed using Seurat and Harmony for clustering and integration, to analyze cellular heterogeneity. This was integrated with Mendelian randomization (MR) using eQTLs from FinnGen and IEU GWAS databases as instrumental variables, and validated through functional experiments including LPS-induced placental explant cultures, qRT-PCR, western blotting, immunohistochemistry, and an\n                      <jats:italic>in vivo<\/jats:italic>\n                      rat intrauterine infection model with AAV-shKLF4 knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We first established a single-cell transcriptomic atlas of preterm mice, identifying nine cell clusters, among which the Ccl2+ fibroblast subpopulation (Ccl2+fib) exhibited significant expansion under pathological conditions. MR analysis identified KLF4 as a genetic risk factor for PTB (OR = 1.32, 95% CI: 1.12\u20131.56), with reverse MR confirming the absence of reverse causality. Clinical validation revealed KLF4-specific upregulation in peripheral blood and placental tissues of PTB patients. Functional studies demonstrated dose-dependent KLF4 upregulation in LPS-induced placental inflammation, while KLF4 knockdown suppressed TNF-\u03b1 and IL-1\u03b2 secretion and reduced apoptosis. In a rat intrauterine infection model, KLF4 knockdown decreased LPS-induced preterm birth rates from 65% to 20%, accompanied by significantly reduced fetal stillbirth rates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals that the fibroblast subpopulation Ccl2+fib contributes to preterm birth through a KLF4-dependent inflammatory regulatory network. KLF4 downregulation significantly reduces infection-induced preterm birth rates and adverse pregnancy outcomes, suggesting that KLF4 is a critical therapeutic target for preterm birth.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1700275","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T06:43:28Z","timestamp":1769755408000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["KLF4 orchestrates a Ccl2+ fibroblast-mediated inflammatory network driving preterm birth"],"prefix":"10.3389","volume":"12","author":[{"given":"Jing","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Obstetrics, The Fourth Hospital of Shijiazhuang, Shijiazhuang","place":["Hebei, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaqing","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, The Second Hospital 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