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Emerging evidence links hemoglobin levels to metabolic disorders, suggesting a potential role in PCOS development. Here, we integrated a large\u2010scale cohort study, Mendelian randomization (A\u00a0genetic tool to infer causal relationships), bioinformatics analyses, and in vitro experiments to investigate the relationship between hemoglobin levels and PCOS. In a cohort of 20 602 women, each 10\u00a0g\u00a0L\n                    <jats:sup>\u22121<\/jats:sup>\n                    elevation in hemoglobin levels is associated with 22% higher odds of PCOS (adjusted odds ratio: 1.22, 95% confidence interval: 1.15\u20131.29,\n                    <jats:italic>P<\/jats:italic>\n                    &lt;\u00a00.001) and PCOS manifestations, particularly hyperandrogenism. Mendelian randomization analysis confirms that higher hemoglobin levels are associated with increased PCOS risk and elevated testosterone levels. The hypoxia\u2010inducible factor 1 (HIF\u20101) pathway is enriched, identifying three testosterone\u2010associated genes (nuclear factor kappa B\n                    <jats:italic>(NFKB1)<\/jats:italic>\n                    , insulin receptor\n                    <jats:italic>(INSR)<\/jats:italic>\n                    , protein kinase C alpha. Colocalization and druggability analysis supports shared genetic regions and confirmed these genes as druggable targets. Upregulation of\n                    <jats:italic>NFKB1<\/jats:italic>\n                    and\n                    <jats:italic>INSR<\/jats:italic>\n                    are confirmed in both blood and ovarian granulosa cells of PCOS patients. The findings demonstrate that higher\u2010end normal hemoglobin levels are associated with increased PCOS risk, potentially through a mechanism of elevating testosterone levels involving the HIF\u20101 pathway.\n                  <\/jats:p>","DOI":"10.1002\/advs.202411679","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T09:14:56Z","timestamp":1739524496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF\u20101 Pathway in Polycystic Ovary Syndrome"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6434-1627","authenticated-orcid":false,"given":"Guiquan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine Women and Children's Hospital School of Medicine Xiamen University Xiamen 361003 China"},{"name":"Xiamen Key Laboratory 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