Polycystic ovary syndrome (PCOS) affects 5–18% of women of reproductive age and is characterized by menstrual irregularities, hyperandrogenism, and polycystic ovaries. The study used a two-sample Mendelian randomization design to assess the causal effects of lipid metabolites, particularly triglyceride-rich lipoproteins, on the risk of PCOS. Elevated triglyceride levels are associated with insulin resistance and cardiovascular risk. The analysis demonstrated a causal effect of lipid-related metabolites on PCOS, with 3-hydroxybutyrate (3-HB), a major ketone body, playing a critical role. In vitro experiments revealed that 3-HB modulates HDAC3 activity, thereby contributing to metabolic and hormonal dysregulation. The study provides evidence linking lipid and ketone body metabolism to PCOS through the 3-HB/HDAC3 pathway.