Granulosa cell RNA-Seq insights into senescence and sphingolipid metabolism disorder in PCOS: aspirin as a potential therapeutic drug.

Abstract

Background: Polycystic ovary syndrome (PCOS) is a pivotal cause of anovulatory infertility and the pathogenesis remains elusive. Cellular senescence and sphingolipid metabolism disorder are closely intertwined, and both have been demonstrated present within the granulosa cells of PCOS, while research on the combined impact of senescence and sphingolipids on PCOS-related anovulation is scarce.

Methods: Here, we leveraged four datasets of PCOS and executed differential gene expression analysis, engaged in WGCNA, and harnessed machine learning algorithms-including RF, SVM-RFE, and LASSO-to deeply explore the key genes that interact with senescence and sphingolipid metabolism in granulosa cells of PCOS. These key genes were subjected to further analysis to construct a diagnostic model, forecast immune cell infiltration, and identify potential agents. Additionally, within the testosterone-stimulated granulosa cells, we validated the expression of key genes, confirmed senescence and sphingolipids dysregulation, and evaluated the therapeutic efficacy of the candidate agent.

Results: Our research pinpointed a set of genes (LYN, PLCG2, STAT5B, MMP9, and IL6R) that showed promise as biomarkers for PCOS-related anovulation and the diagnostic nomogram was developed. These biomarkers were linked to various immune cell types infiltration. In testosterone-stimulated granulosa cells, we observed increased expression of these biomarkers, accompanied by signs of senescence and changes in sphingolipids. Importantly, the potential agent aspirin displayed the ability to ameliorate these two processes.

Conclusion: This study highlighted the important value of genes associated with senescence and sphingolipids dysregulation in PCOS. Aspirin targeting senescence could be a promising therapeutic drug for addressing anovulation associated with PCOS.