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Identification of ferroptotic genes and phenotypes in idiopathic nonobstructive azoospermia
Chen Liao1,2, Tian-Wen Peng1,2, Xiao-Min Li1,2
1Department of Obstetrics and Gynecology, Center for Reproductive Medicine; Guangdong Provincial Key Laboratory for Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affifiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
Abstract:
Effective treatments for nonobstructive azoospermia (NOA), which affects 1% of all men globally, are limited by undefined pathogenic mechanisms, especially in idiopathic NOA (iNOA). Here, we tried to identify the functional ferroptosis-related genes and phenotypes involved in iNOA. Differentially expressed ferroptotic genes were identified from iNOA mRNA microarray datasets by bioinformatic analyses, and these ferroptotic genes were subsequently filtered by various algorithms. Then, receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic ability of the abovementioned genes for iNOA. Generally, 11 differentially expressed ferroptotic genes were downregulated, and five genes were upregulated in iNOA samples. Four genes, including DUSP1, GPX4, HSD17B11, and SLC2A8, were technically selected and determined to be potential biomarkers for iNOA. Subsequently, similar expression levels were validated at both the RNA and protein levels in the iNOA specimens. Finally, morphologic and biochemical assays were applied to define the ferroptotic phenotypes in testes. The ferroptotic features, like shrunken mitochondria with electron-dense membranes and a reduction in cristae were observed across various cell types within iNOA patients, accompanied by the overload of ferrous ions and increased lipid peroxidation production. Our findings demonstrated that these ferroptosis genes could be involved in the underlying pathogenesis mechanisms of iNOA by regulating ferroptosis and serve as potential diagnostic biomarkers. Also, the ferroptotic phenotypes were identified in iNOA patients.
Insights
Researchers identified ferroptosis-related genes and cellular changes in idiopathic nonobstructive azoospermia (iNOA). Four genes (DUSP1, GPX4, HSD17B11, SLC2A8) show potential as diagnostic biomarkers for iNOA.
Area of Science:
- Reproductive biology
- Cellular biology
- Biochemistry
Background:
- Nonobstructive azoospermia (NOA) affects 1% of men globally, with limited treatment options due to poorly understood mechanisms, particularly in idiopathic NOA (iNOA).
- Ferroptosis, a regulated form of cell death, is increasingly recognized for its role in various biological processes and diseases.
Purpose of the Study:
- To identify functional ferroptosis-related genes and phenotypes implicated in the pathogenesis of idiopathic nonobstructive azoospermia (iNOA).
- To evaluate the diagnostic potential of identified ferroptosis genes as biomarkers for iNOA.
Main Methods:
- Bioinformatic analysis of iNOA mRNA microarray datasets to identify differentially expressed ferroptosis-related genes.
- Receiver operating characteristic (ROC) curve analysis to assess diagnostic accuracy of candidate genes.
- Validation of gene and protein expression in iNOA specimens.
- Morphologic and biochemical assays to characterize ferroptotic phenotypes in testicular tissues.
Main Results:
- Eleven ferroptosis genes were downregulated and five were upregulated in iNOA samples.
- Four genes (DUSP1, GPX4, HSD17B11, SLC2A8) were identified as potential diagnostic biomarkers for iNOA.
- Ferroptotic features, including mitochondrial changes, ferrous ion overload, and increased lipid peroxidation, were observed in iNOA testes.
Conclusions:
- Ferroptosis-related genes are implicated in the pathogenesis of iNOA.
- The identified genes (DUSP1, GPX4, HSD17B11, SLC2A8) represent potential diagnostic biomarkers for iNOA.
- Specific ferroptotic cellular phenotypes are present in iNOA patients, offering insights into disease mechanisms.
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