Integrative metabolomics and proteomics reveal early cardiovascular risk signatures in PCOS female offspring

Background
Polycystic ovary syndrome (PCOS) is associated with metabolism abnormalities and increased cardiovascular disease (CVD) risk. This study aimed to further investigate cardiovascular metabolism alterations specifically in the female offspring of PCOS patients using metabolomics and proteomics, and to identify potential early CVD-related biomarkers in this population.

Methods
A total of 40 female offspring of PCOS patients and 40 female offspring of non-PCOS individuals (4–6 years old) were enrolled in this study. Cardiovascular risk features including height, weight, body mass index (BMI), blood pressure, glycemic and lipid parameters were assessed. Untargeted metabolomics and the Olink proteomics were applied to identify alterations in metabolites and CVD-related proteins. A further in-depth analysis of metabolomics and proteomics was conducted.

Results
Lipid indicators, including Total Cholesterol（TC）, Low-Density Lipoprotein Cholesterol（LDL-C）, and high-density lipoprotein cholesterol (HDL-C), as well as γ-glutamyl transferase (GGT), a marker of liver function were significantly elevated in the female offspring of PCOS patients compared to the female offspring of non-PCOS women. Metabolomic profiling revealed significant alterations in lipid metabolites, particularly in glycerophospholipids and fatty acids, in the female offspring of PCOS patients. Additionally, elevated levels of CVD-related proteins, including proprotein convertase subtilisin/kexin type (PCSK9), tissue factor pathway inhibitor (TFPI), secretoglobin family 3A member 2 (SCGB3A2), junctional adhesion molecule A (JAM-A), interleukin-1 receptor-like 1 (ST2) and epidermal growth factor receptor (EGFR) were observed, with significant correlations between these proteins and the altered lipid metabolites. We conducted mediation analysis and identified several metabolites and proteins that mediate cardiovascular risk. A a combined metabolite and protein panel consisting of phospholipids (PIs), lysophosphatidylcholines (LysoPCs), and CVD-related proteins demonstrated an area under the curve (AUC) of 0.93 based on receiver operating characteristic (ROC) curve analysis, effectively differentiating female offspring with hyperlipidemia.

Conclusions
Female offspring of PCOS patients exhibit distinct lipid metabolic and protein profiles that suggest early cardiovascular-related alterations. These findings support the potential value of early metabolic monitoring in this population and highlight the need for longitudinal studies to determine whether these alterations translate to increased cardiovascular risk in adulthood. The identified metabolite and protein biomarkers may serve as tools for early risk assessment, pending prospective validation of their long-term predictive value.