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Inflammation is implicated in many diseases, including male and female infertility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study employed Mendelian randomization (MR) with two-sample, bidirectional, and mediation approaches to explore the relationship between circulating inflammatory proteins and infertility. Causal analysis was conducted using inverse variance-weighted (IVW) and MR-Egger regression, supplemented by enrichment analysis, protein-protein interaction (PPI) network exploration, and drug signature analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings identified a significant positive correlation between C-X-C motif chemokine 6 (CXCL6) and male infertility, positioning CXCL6 as a potential therapeutic target or biomarker. No causal links were detected between circulating inflammatory proteins and female infertility post-FDR adjustment. Minor mediation effects were observed for metabolites such as androstenediol monosulfate, arachidonoylcholine, and serum phosphate to glycerol ratio. Cytokine-related pathways emerged as significant in both male and female infertility. Gene-drug interaction analysis highlighted the need for further investigation of pioglitazone in treating female infertility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study establishes a potentially causal relationship between CXCL6 and male infertility, suggesting its potential as a drug target or molecular biomarker. The integrative approach combining causal inference with molecular pathway and drug interaction analysis opens new avenues for understanding and treating infertility.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1448530","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T05:10:53Z","timestamp":1740460253000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Causal inference of inflammatory proteins in infertility: a Mendelian randomization 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