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Updated: Sep 9, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Single-cell, spatial and bulk transcriptome data analysis revealed LINC00467-mediated Sertoli cell ferroptosis is a
Hao Bo1, Fang Zhu2, Xueheng Zhao2
1NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China.
Abstract:
Human spermatogenesis is an important physiological process related to programmed cell death. However, which type of programmed cell death playing a key role in normal and abnormal human spermatogenesis remains obscure. This study integrated single-cell, bulk RNA and spatial transcriptome data analysis and found that the ferroptosis signal plays a potential role in spermatogenesis and significantly elevate in testicular samples from humans with non-obstructive azoospermia (NOA) due to various factors. In addition, the increased levels of GPX4-dependent ferroptosis in Sertoli cells is a common feature of NOA samples and inhibiting ferroptosis of Sertoli cells in azoospermia patients can improve the functional status of Sertoli cells. Based on weighted correlation network analysis (WGCNA), correlation analysis, differential expression analysis and in vitro experiments, we confirmed that long non-coding RNA (lncRNA) LINC00467 is a key factor in regulating ferroptosis in Sertoli cells. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) experiments showed that LINC00467 can be used to predict sperm retrieval outcomes in NOA patients. In summary, this study reveals and verifies that the level of ferroptosis apparently elevates in Sertoli cells is a novel mechanism for NOA patients, and proposes that ferroptosis-related gene LINC00467 is potential biomarker and therapeutic target for NOA.
Insights
Ferroptosis, a type of programmed cell death, is elevated in non-obstructive azoospermia (NOA). Targeting ferroptosis in Sertoli cells, regulated by LINC00467, may improve male fertility.
Area of Science:
- Reproductive biology
- Cell death mechanisms
- Molecular genetics
Background:
- Spermatogenesis involves programmed cell death, but the specific type's role in human fertility is unclear.
- Non-obstructive azoospermia (NOA) is a major cause of male infertility, often linked to testicular dysfunction.
Purpose of the Study:
- To investigate the role of ferroptosis in human spermatogenesis and NOA.
- To identify key regulators of ferroptosis in Sertoli cells relevant to NOA.
- To evaluate LINC00467 as a biomarker for sperm retrieval in NOA patients.
Main Methods:
- Integrated analysis of single-cell, bulk RNA, and spatial transcriptomics data.
- Weighted gene co-expression network analysis (WGCNA) and correlation analysis.
- In vitro experiments and quantitative real-time polymerase chain reaction (qRT-PCR).
Main Results:
- Ferroptosis signaling is elevated in human spermatogenesis and significantly increased in NOA testicular samples.
- GPX4-dependent ferroptosis in Sertoli cells is a hallmark of NOA, and its inhibition improves Sertoli cell function.
- The long non-coding RNA (lncRNA) LINC00467 was identified as a key regulator of ferroptosis in Sertoli cells.
- LINC00467 levels correlate with sperm retrieval outcomes in NOA patients.
Conclusions:
- Elevated ferroptosis in Sertoli cells represents a novel mechanism contributing to NOA.
- LINC00467 is a potential biomarker for predicting sperm retrieval success and a therapeutic target for NOA.
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