Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from six genome-wide association studies (GWASs) on plasma proteome. Genetic associations with PCOS were obtained from a large-scale GWAS meta-analysis, FinnGen cohort, and UK Biobank. Colocalization analyses were performed to prioritize the causal role of candidate proteins. Protein-protein interaction (PPI) and druggability evaluation assessed the druggability of candidate proteins. We evaluated the enrichment of tier 1 and 2 candidate proteins in individuals with PCOS and a mouse model and explored the potential application of the identified drug target. Genetically predicted levels of 65 proteins exhibited associations with PCOS risk, with 30 proteins showing elevated levels and 35 proteins showing decreased levels linked to higher susceptibility. PPI analyses revealed that FSHB, POSTN, CCN2, and CXCL11 interacted with targets of current PCOS medications. Eighty medications targeting 20 proteins showed their potential for repurposing as therapeutic targets for PCOS. EGLN1 levels were elevated in granulosa cells and the plasma of individuals with PCOS and in the plasma and ovaries of dehydroepiandrosterone (DHEA)-induced PCOS mouse model. As an EGLN1 inhibitor, administration of roxadustat in the PCOS mouse model elucidated the EGLN1-HIF1α-ferroptosis axis in inducing PCOS and validated its therapeutic effect in PCOS. Our study identifies candidate proteins causally associated with PCOS risk and suggests that targeting EGLN1 provides a promising treatment strategy.

中文翻译：

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蛋白质组范围的孟德尔随机化和功能研究揭示了多囊卵巢综合征的治疗靶点


多囊卵巢综合征 （PCOS） 是一种影响全球大部分女性的内分泌综合征。这项蛋白质基因组学和功能研究旨在发现 PCOS 的候选治疗靶点。我们使用双样本孟德尔随机化分析全面研究了循环蛋白与 PCOS 之间的因果关系。顺式蛋白数量性状位点来源于血浆蛋白质组的 6 项全基因组关联研究 （GWASs）。与 PCOS 的遗传关联来自大规模 GWAS 荟萃分析、FinnGen 队列和英国生物样本库。进行共定位分析以优先考虑候选蛋白的因果作用。蛋白质-蛋白质相互作用 （PPI） 和成药性评价评估候选蛋白的成药性。我们评估了 PCOS 个体和小鼠模型中 1 层和 2 层候选蛋白的富集，并探索了已确定的药物靶点的潜在应用。遗传预测的 65 种蛋白质水平与 PCOS 风险相关，其中 30 种蛋白质显示水平升高，35 种蛋白质显示水平降低与较高的易感性有关。PPI 分析显示 FSHB 、 POSTN 、 CCN2 和 CXCL11 与当前 PCOS 药物的靶点相互作用。靶向 20 种蛋白质的 80 种药物显示出它们作为 PCOS 治疗靶点的潜力。EGLN1 水平在 PCOS 个体的颗粒细胞和血浆以及脱氢表雄酮 （DHEA） 诱导的 PCOS 小鼠模型的血浆和卵巢中升高。作为 EGLN1 抑制剂，在 PCOS 小鼠模型中施用罗沙司他阐明了诱导 PCOS 的 EGLN1-HIF1α-铁死亡轴，并验证了其在 PCOS 中的治疗效果。 我们的研究确定了与 PCOS 风险有因果关系的候选蛋白，并表明靶向 EGLN1 提供了一种有前途的治疗策略。