Targeted metabolomics in PCOS mice identifies hippuric acid as a therapeutic metabolite

Polycystic ovary syndrome (PCOS) represents a complex endocrine disorder with profound detrimental effects on women's reproductive and metabolic health, yet the absence of specific pharmacotherapeutic interventions has resulted in a significant therapeutic gap. To elucidate the metabolic alterations in PCOS, we conducted a comprehensive targeted metabolomics analysis of plasma samples from healthy control mice and PCOS model mice, examining a panel of 197 metabolites spanning diverse metabolic classes. Our analysis revealed substantial metabolic differences between the groups, with organic acids, amino acids, and fatty acids emerging as the most abundant metabolite classes in both cohorts. Among the 197 metabolites analyzed, 86 demonstrated a Variable Importance in Projection (VIP) score > 1, with univariate analysis confirming 76 distinct metabolites showing significant alterations. Notably, the PCOS group exhibited marked increases in metabolites such as tartaric acid and docosapentaenoic acid, while hippuric acid showed the most pronounced reduction. Pathway enrichment analysis identified significant perturbations in key metabolic pathways, including amino acid metabolism, fatty acid oxidation, and the urea cycle in PCOS mice. The exogenous administration of hippuric acid led to a significant amelioration of ovarian pathology in PCOS mice, highlighting its promising therapeutic potential. These findings provide crucial insights into the altered metabolic landscape of PCOS, identifying potential biomarkers and therapeutic targets, with particular emphasis on the promising therapeutic role of hippuric acid in mitigating PCOS pathology, thereby offering a valuable avenue for further investigation and clinical translation.