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Integrative Single-Cell Analysis Reveals Iron Overload-Induced Senescence and Metabolic Reprogramming in Ovarian Endometriosis-Associated Infertility

ABSTRACT: Endometriosis, particularly ovarian endometriosis (OE), significantly impacts fertility by often leading to decreased oocyte quality and impaired ovarian function. Iron overload has been identified as a critical factor driving disease progression in endometriosis lesions. This study aims to investigate the effects of iron overload on follicular function in OE-associated infertility (OEI). Using single-cell sequencing technologies, we first identified oocyte dysfunction in OEI patients and established a single-cell atlas of iron overload in follicular fluid prior to ovulation in OEI patients. This atlas revealed dynamic changes in iron metabolism and identified iron-induced senescence phenotypes. We also examined the differentiation trajectories of granulosa cells and the relationship between macrophage M1/M2 phenotypes and iron metabolism. Additionally, we utilized Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) to construct a spatial transcriptomic map of iron-overloaded mouse ovaries, uncovering various enriched senescence phenotypes. Finally, we extended our findings by exploring the dynamics of iron metabolism imbalance in aging human ovaries. Overall, these findings enhance our understanding of iron overload-related cellular interactions and molecular characteristics in ovarian pathology, providing new therapeutic targets for improving oocyte quality in OEI patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276193 | GEO | 2025/08/27

REPOSITORIES: GEO

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Project description:BACKGROUND: Endometriosis is a common benign gynaecological disorder. A number of studies have confirmed that the occurrence of disease in endometriosis patients is associated with metabolic changes in biological fluids and tissues. We set out to investigate the metabolic characteristics of follicular fluid in patients with ovarian endometriosis undergoing in vitro fertilization (IVF).METHODS: The current research project is an exploratory cohort study on endometriosis. A total of 19 infertile patients with ovarian endometriosis diagnosed by laparoscopy were enrolled in this study and 23 age- and BMI-matched controls (women with infertility due to male or tubal factors). All the patients underwent IVF treatment with a gonadotropin-releasing hormone antagonist protocol and completed follicular fluid (FF) collection at oocyte retrieval. The metabolomics of FF samples was analyzed by ultra high performance liquid chromatography-orbitrap exploris-mass spectrometer (UHPLC-OE-MS). The best combination of biomarkers was then selected by performing stepwise logistic regression analysis with backward elimination. RESULTS: Fifteen metabolites were identified as biomarkers associated with endometriosis. A final model containing 8-hydroxy-2-deoxyguanosine, biotin, n-acetyl-L-methionine and n-methylnicotinamide was constructed. Receiver operating characteristic analysis confirmed the value of these parameters in diagnosing endometriosis, with a sensitivity of 94.7% and a specificity of 95.7%. Analysis of fortification via the Kyoto Encyclopedia of Genes and Genome showed that 15 metabolites were enriched in 8 metabolic pathways.CONCLUSION: Metabolomics based on UHPLC-OE-MS effectively characterized the metabolomics analysis of FF in patients with ovarian endometriosis. These findings may provide a new basis for a better understanding of how diseases progress and for the discovery of new biomarkers.

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Integrative Single-Cell Analysis Reveals Iron Overload-Induced Senescence and Metabolic Reprogramming in Ovarian Endometriosis-Associated Infertility

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