Dataset Information

Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome.

ABSTRACT:

Background

Numerous studies have suggested that ferroptosis plays a significant role in the development of polycystic ovary syndrome (PCOS), but the mechanism remains unclear.

Methods

In this study, we explored the role of ferroptosis-related genes in the pathogenesis of PCOS using a comprehensive bioinformatics method. First, we downloaded several Gene Expression Omnibus (GEO) datasets and combined them into a meta-GEO dataset. Differential expression analysis was performed to screen for significant ferroptosis-related genes between the normal and PCOS samples. The least absolute shrinkage selection operator regression and support vector machine-recursive feature elimination were used to select the best signs to construct a PCOS diagnostic model. Receiver operating characteristic curve analysis and decision curve analysis were applied to test the performance of the model. Finally, a ceRNA network-related ferroptosis gene was constructed.

Results

Five genes, namely, NOX1, ACVR1B, PHF21A, FTL, and GALNT14, were identified from 10 differentially expressed ferroptosis-related genes to construct a PCOS diagnostic model. Finally, a ceRNA network including 117 lncRNAs, 67 miRNAs, and five ferroptosis-related genes was constructed.

Conclusion

Our study identified five ferroptosis-related genes that may be involved in the pathogenesis of PCOS, which may provide a novel perspective for the clinical diagnosis and treatment of PCOS.

SUBMITTER: Lin S

PROVIDER: S-EPMC9981782 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome.

Lin Shuang S Jin Xin X Gu He H Bi Fangfang F

Frontiers in medicine 20230217

<h4>Background</h4>Numerous studies have suggested that ferroptosis plays a significant role in the development of polycystic ovary syndrome (PCOS), but the mechanism remains unclear.<h4>Methods</h4>In this study, we explored the role of ferroptosis-related genes in the pathogenesis of PCOS using a comprehensive bioinformatics method. First, we downloaded several Gene Expression Omnibus (GEO) datasets and combined them into a meta-GEO dataset. Differential expression analysis was performed to sc ...[more]

PMID: 36873892

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Project description:BackgroundPoor oocyte quality remains one of the major challenges for polycystic ovary syndrome (PCOS) patients during in vitro fertilization (IVF) treatment. Granulosa cells (GCs) in PCOS display altered functions and could cause an unfavorable microenvironment for oocyte growth and maturation. Ferroptosis is a new form of programmed cell death, but its role in PCOS has been largely unclarified.MethodsFerroptosis-related differentially expressed genes (DEGs) of GCs in women with PCOS were identified by bioinformatic analyses of GSE155489 and GSE168404 datasets. Functional enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Core ferroptosis-related genes were further screened by random forest, and evaluated for diagnostic value by receiver operating characteristic curve analyses. Gene expression was validated by real-time quantitative polymerase chain reaction of collected GC samples, and analyzed for association with oocyte quality. In addition, gene regulatory network was constructed based on predicted RNA interactions and transcription factors, while potential therapeutic compounds were screened through molecular docking with crystallographic protein structures.ResultsA total of 14 ferroptosis-related DEGs were identified. These DEGs were mainly enriched in reactive oxygen species metabolic process, mitochondrial outer membrane, antioxidant activity as well as ferroptosis and adipocytokine signaling pathways. Eight core ferroptosis-related genes (ATF3, BNIP3, DDIT4, LPIN1, NOS2, NQO1, SLC2A1 and SLC2A6) were further selected in random forest model, which showed high diagnostic performance for PCOS. Seven of them were validated in GC samples, and five were found to be significantly and positively correlated with one or more oocyte quality parameters in PCOS patients, including oocyte retrieval rate, mature oocyte rate, normal fertilization rate, and good-quality embryo rate. Gene regulatory network revealed JUN and HMGA1 as two important transcription factors, while dicoumarol and flavin adenine dinucleotide were predicted as small molecules with therapeutic potential.ConclusionsThis is the first comprehensive report to study the differential expression of ferroptosis-related genes in GCs of PCOS and their clinical relevance with oocyte quality. Our findings could provide novel insights on the potential role of GC ferroptosis in PCOS pathogenesis, diagnosis, and targeted treatment.

Project description:Background and objectivePCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway.Materials and methodsC57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR.ResultsCompared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group.ConclusionOur study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS via the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS.

Project description:BackgroundPolycystic ovary syndrome (PCOS) is defined by oligo/anovulation, hyperandrogenism, and polycystic ovaries with uncertain pathogenesis. The proteome represents a substantial source of therapeutic targets, and their coding genes may elucidate the mechanisms underlying PCOS. However, reports on the profiles of the human plasma protein-coding genes and PCOS are limited. Here, we aimed to investigate novel biomarkers or drug targets for PCOS by integrating genetics and the human plasma proteome.MethodsOur study acquired the protein quantitative trait loci from DECODE Genetics, offering 4,907 proteins in 35,559 individuals while obtaining PCOS summary statistics by accessing the FinnGen biobank (1,639 cases and 218,970 controls) and the genome-wide association study catalog (797 cases and 140,558 controls). Herein, we sequentially used two-sample Mendelian randomization (MR) analyses and colocalization to verify the causal link between candidate proteins, their coding genes, and PCOS. Further PCOS data download was conducted by accessing the Gene Expression Omnibus and Zenodo platforms. Gene expression level analysis, pathway enrichment analysis, immune cell infiltration, and transcription factor prediction were performed, aiming at detecting specific cell types with enriched expression and exploring potential optimized treatments for PCOS.ResultsMR analysis revealed 243 protein-coding genes with a causal relationship to PCOS risk, of which 12 were prioritized with the most significant evidence. Through colocalization analysis, three key genes, CUB domain-containing protein 1 (CDCP1), glutaredoxin 2 (GLRX2), and kirre-like nephrin family adhesion molecule 2 (KIRREL2), were identified. Subsequently, the three genes were strongly related to immune function and metabolism in terms of biological significance. In single-cell analysis, the expression levels of genes in ovarian theca cells were explored.ConclusionOverall, three protein-coding genes (CDCP1, GLRX2, and KIRREL2) may be related to a higher PCOS risk, suggesting that they may be entry points for exploration of PCOS pathogenesis and treatment, warranting further clinical investigations.

Dataset Information

Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome.

Background

Methods

Results

Conclusion

Publications

Relationships of ferroptosis-related genes with the pathogenesis in polycystic ovary syndrome.

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