SIRT1 inhibits ferroptosis of granulosa cells in polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder among adolescent females and women of reproductive age. Ferroptosis is a newly recognized form of programmed cell death characterized by lipid peroxidation, which is iron-dependent and involves an elevation in cellular reactive oxygen species (ROS). In this study, we investigated the role of ferroptosis-related genes in PCOS through integrative bioinformatics and experimental validation. Differential expression analysis of Gene Expression Omnibus (GEO) datasets, combined with machine learning and Cytoscape, identified SIRT1 as a candidate gene linked to ferroptosis. Analysis of GEO datasets showed that SIRT1 expression was decreased by 1.32-fold in PCOS granulosa cells compared with controls (p < 0.05). Subsequently, we utilized scRNA-seq data analysis and performed cell communication analyses for a more in-depth understanding. Functional assays revealed that SIRT1 overexpression or pharmacological activation by SRT1720 significantly decreased lipid peroxidation and reactive oxygen species levels, thereby alleviating ferroptosis (p < 0.05). Mechanistically, co-immunoprecipitation indicated that SIRT1 interacted with Nrf2, and molecular docking suggested potential SIRT1-binding compounds. Collectively, these findings indicate that SIRT1 suppresses ferroptosis in granulosa cells via Nrf2 deacetylation, providing new insight into PCOS pathogenesis and suggesting SIRT1 as a potential therapeutic target.