Human Serum Microvesicles as Mediators of PCOS-Related circRNAs Targeting FOXO1/NF-κB Pathways: Implications for PCOS Formation and Its Mental and Physical Health Impact

Abstract

Purpose: Polycystic ovary syndrome (PCOS), a multifaceted endocrine disorder, manifests through a spectrum of symptoms including infertility, hyperandrogenemia, and insulin resistance, underpinned by chronic inflammation and disrupted glycolipid metabolism. Despite extensive research, the intricate pathogenesis of PCOS remains elusive. Microvesicles (MVs), ubiquitous in cellular communication, could hold the key to understanding and potentially treating PCOS-related infertility by mediating the expression of PCOS-associated circRNAs. This study explores the role of serum MVs in conveying circRNAs that target the FOXO1/NF-κB signaling pathways, contributing to the etiology of PCOS and offering novel therapeutic insights. Methods: Serum samples from PCOS patients and infertile women without PCOS were analyzed for hormone levels and prepared for MV isolation. The identification of MVs was performed using Western blot, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). High-throughput whole-transcriptome sequencing provided a circRNA expression profile from these MVs, highlighting their involvement in inflammatory signaling pathways. In vitro assays on KGN cells were conducted to assess the impact of PCOS MVs on cell proliferation and to elucidate the involvement of circRNA in PCOS pathology. Results: Differential expression of circRNAs in serum MVs was observed between PCOS patients and control subjects. The incorporation of PCOS-derived MVs into KGN cells resulted in suppressed cell proliferation. Moreover, the expression of key inflammatory mediators, FOXO1 and NF-κB, was significantly elevated in PCOS, indicating their regulatory involvement through circRNA-mediated pathways. Conclusion: The study underscores the pivotal role of circRNA-loaded MVs in modulating FOXO1 and NF-κB activation, thereby influencing the pathophysiological landscape of PCOS. These findings highlight a novel mechanism through which PCOS-induced changes in ovarian function and infertility may be mediated, offering promising avenues for therapeutic intervention. Importantly, this research also calls attention to the broader implications of PCOS on mental and physical health, advocating for an integrated approach to understanding and managing the syndrome, with a focus on the intricate web of biological and psychological factors contributing to its development and progression.