{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T16:24:15Z","timestamp":1793982255710,"version":"4.8.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recurrent spontaneous abortion (RSA) significantly impacts women\u2019s health, yet the underlying biological mechanisms remain poorly defined. Understanding the molecular contributors to RSA is crucial for developing targeted interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to investigate the causal relationships between plasma proteins and RSA, focusing on the identification of potential therapeutic targets through multi-omic approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We utilized two-sample Mendelian randomization (MR) analyses integrating genome-wide association study (GWAS) data for both plasma proteins and RSA. Proteomic data were sourced from the UK Biobank-Plasma Proteome Project and deCODE Health Study. We further validated our findings through both bulk and single-cell RNA sequencing of clinical specimens, alongside quantitative real-time polymerase chain reaction and immunohistochemistry. A phenome-wide association study was also conducted to assess the safety and broader implications of identified targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analyses identified the interleukin 6 receptor (IL6R) as a key candidate, with elevated plasma levels correlating with increased RSA risk. Furthermore, IL6R was found to be upregulated in RSA-related endometrial and decidual tissues. The phenome-wide association study provided insights into potential side effects and additional therapeutic indications for IL6R.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IL6R upregulation is mechanistically implicated in the pathogenesis of RSA, establishing it as a validated causal biomarker and a potentially actionable therapeutic target. This study not only highlights the role of IL6R in RSA but also supports its development into a therapeutic strategy with a comprehensive safety profile.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1659251","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T05:30:45Z","timestamp":1759383045000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Integrative genetic and multi-omics analysis reveals the interleukin-6 receptor\u2019s role in recurrent spontaneous 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