ORIGINAL RESEARCH article
Front. Genet.
Sec. Human and Medical Genomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1626992
Identification of Hypoxia-Related Diagnostic Biomarkers and Immune Signatures in Diminished Ovarian Reserve
Provisionally accepted
- 1The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
- 2Hunan University of Chinese Medicine, Changsha, China
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Background: Diminished ovarian reserve (DOR) becomes more common with age, and hypoxia is a key cause of apoptosis in ovarian granulosa cells. This study investigated the genetic links between hypoxia and DOR. Methods: The GSE87201 dataset for DOR was sourced from Gene Expression Omnibus database, normalized for common differentially expressed genes (Co-DEGs), and identified Hypoxia-related differentially expressed genes (HRDEGs) via GeneCards; Receiver Operating Characteristic (ROC) curves evaluated HRDEGs' diagnostic value, and protein-protein interaction networks were visualized with STRING and Cytoscape. Enrichment analyses included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and immune cell infiltration compared ovarian reserve groups. A granulosa cell injury model was created using 4-hydroperoxycyclophosphamide (4-HC), with Quantitative real-time PCR and Western Blot measuring FANCI and KAT2A expression, and Cell Counting Kit-8 assays and flow cytometry assessing cell proliferation and apoptosis. Results: Twelve hypoxia-related genes were differentially expressed between low ovarian reserve (LOR) and high ovarian reserve (HOR), with 17 linked to DOR; eight pathways differed between LOR and HOR. Six hub genes (FANCI, KAT2A, TACC3, TPX2, VHL, WSB1) were enriched in Fanconi anemia and HIF-1 pathways, affecting microtubules, spindle formation, and cytoskeleton dynamics during mitosis. Immune cell infiltration analysis showed significant differences, with FANCI, TACC3, and TPX2 correlating with immune populations. The DOR group had increased FANCI and KAT2A levels compared to Control (two of the several genes that were matched were randomly selected for validation), alongside reduced cell viability and increased apoptosis. Conclusion: FANCI, KAT2A, TACC3, TPX2, VHL, and WSB1 may be diagnostic biomarkers for DOR, providing novel insights for future research into the pathogenesis of hypoxia-induced DOR.
Keywords: diminished ovarian reserve, Hypoxia-related gene, high ovarian reserve, low ovarian reserve, Immune Cell Infiltration
Received: 12 May 2025; Accepted: 17 Jul 2025.
Copyright: © 2025 Song, Ni, Ma, Zhong, Liu, Kuang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ping Li, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
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