Exploring the regulatory mechanisms of reproductive dysfunction in obese patients with PCOS

Abstract

Abstract Polycystic ovary syndrome (PCOS) is a complex endocrine disorder often worsened by obesity, leading to chronic inflammation, metabolic dysregulation, and reproductive dysfunction. This study aims to uncover the molecular mechanisms underlying reproductive dysfunction in obese PCOS patients by identifying key regulatory genes, pathways, and immune interactions, with a focus on cross-tissue regulators and potential therapeutic targets. We analyzed transcriptomic data from multiple datasets, including GSE43322, GSE43264, GSE124226, GSE54250, GSE48301, and GSE114419. Differential gene expression analysis, weighted gene co-expression network analysis, immune infiltration profiling, and pathway enrichment were performed. Cross-tissue comparisons identified overlapping genes, and molecular docking was conducted to screen FDA-approved small molecules targeting key regulators. qPCR was conducted on PBMCs from 5 PCOS patients and 5 controls to validate the expression of Cytoplasmic Polyadenylation Element Binding Protein 4 (CPEB4). CPEB4 was identified as a critical cross-tissue regulator linking systemic metabolic dysregulation with local ovarian dysfunction. It was enriched in pathways related to oocyte maturation and meiosis, highlighting its role in reproductive health. Immune infiltration analysis revealed increased pro-inflammatory M1 macrophages and decreased anti-inflammatory M2 macrophages in adipose tissue, contributing to chronic inflammation. qPCR results confirmed a significant upregulation of CPEB4 in PBMCs from PCOS patients compared to controls, with a 2.8-fold increase (p < 0.01). Molecular docking identified several small molecules with high binding affinity to CPEB4, including 6-aminohexanoic acid and N-hydroxyacetamide, as potential therapeutic candidates. This study provides novel insights into the pathophysiology of obese PCOS, emphasizing the role of CPEB4 as a key regulator connecting metabolic and reproductive dysfunction. The qPCR validation in PBMCs further supports the systemic relevance of CPEB4 in PCOS. Targeting CPEB4 with small-molecule therapeutics offers a promising strategy for addressing both systemic and reproductive abnormalities in obese patients with PCOS.

Keywords

• Polycystic ovary syndrome
• Transcriptomics
• Immune infiltration
• Molecular docking
• Therapeutic targets