SETX 功能缺失通过影响细胞衰老进而导致早发性卵巢功能不全

doi:10.3969/j.issn.1006-7795.2026.03.021

首都医科大学学报 ›› 2026, Vol. 47 ›› Issue (3): 579-587.doi: 10.3969/j.issn.1006-7795.2026.03.021

SETX 功能缺失通过影响细胞衰老进而导致早发性卵巢功能不全

郑智¹,孙玉君¹,李雨筱¹,何琳¹,侯丽莎¹,李琳^1*#,褚春芳^2*#

1.首都医科大学附属北京妇产医院中心实验室，北京 100006； 2.首都医科大学附属北京妇产医院妇科，北京 100026

收稿日期:2025-12-22 修回日期:2026-03-29 出版日期:2026-06-21 发布日期:2026-06-26
通讯作者: 李琳, 褚春芳 E-mail:linlithu@ccmu.edu.cn；chuchunfang@ccmu.edu.cn
基金资助:
国家自然科学基金资助项目（82171628），北京市医院管理中心青苗计划资助项目（QML20201401）。

The role of SETX deficiency in driving cellular senescence and premature ovarian insufficiency

Zheng Zhi ¹, Sun Yujun ¹, Li Yuxiao ¹, He Lin ¹, Hou Lisha ¹, Li Lin^1*#, Chu Chunfang^2*#

1.Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, China; 2. Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China

Received:2025-12-22 Revised:2026-03-29 Online:2026-06-21 Published:2026-06-26
Supported by:
This study was supported by the National Natural Science Foundation of China (82171628), and Beijing Hospitals Authority Youth Program (QML20201401).

摘要/Abstract

摘要： 目的探讨 Senataxin（SETX）功能缺失导致早发性卵巢功能不全（premature ovarian insufficiency, POI）的潜在分子机制。方法对POI患者行外显子组测序并分析测序结果，通过Sanger测序验证找到的基因变异。采用小干扰 RNA 技术敲低293FT细胞中SETX 表达，通过转录组测序分析 SETX 缺失引发的整体转录变化，并结合功能富集分析解析其生物学意义。采用实时逆转录聚合酶链式反应（real-time reverse transcription polymerase chain reaction, RT-qPCR）对部分与细胞衰老和细胞周期相关的基因进行验证。结果外显子组测序发现一例POI患者携带SETX截短变异：c.4005_4008del (p. Val1336Glufs*7) ，该变异预测导致SETX蛋白截短。因此本研究通过在细胞中敲低SETX揭示了SETX截短变异的致病机制。SETX 敲低后细胞整体转录特征发生显著改变，差异表达基因广泛涉及应激反应、信号转导及细胞结构相关过程。功能富集分析结果显示，丝裂源活化蛋白激酶信号通路、晚期糖基化终末产物-受体信号通路及细胞因子-受体相互作用等通路显著富集。qPCR结果提示，SETX 敲低后细胞周期蛋白D1、沉默信息调节因子1和根蛋白表达下调，而生长停滞和DNA损伤诱导α蛋白、β蛋白及Krüppel样因子2上调。结论 SETX 功能缺失可显著重塑细胞转录程序，激活应激反应及细胞衰老相关信号通路，提示 SETX 在维持细胞稳态及延缓衰老进程中具有重要作用，为进一步理解其在细胞衰老及 POI 中的潜在分子机制提供了新的依据。

关键词: SETX, 早发性卵巢功能不全, 全外显子组测序, 细胞衰老, 转录组测序, 基因敲低, 功能富集分析

Abstract: Objective To investigate the molecular mechanisms by which siRNA-mediated knockdown of Senataxin (SETX) contributes to premature ovarian insufficiency (POI). Methods Whole-exome sequencing was conducted in patients with premature ovarian insufficiency to screen for candidate pathogenic variants, followed by validation using Sanger sequencing. SETX expression was knocked down in 293FT cells using small interfering RNA (siRNA). Transcriptome sequencing (RNA-seq) was performed to analyze the global transcriptional changes induced by SETX knockdown. Functional enrichment analysis was conducted to interpret the biological implications. The expression of genes related to cellular senescence and the cell cycle was validated by real-time reverse transcription polymerase chain reaction (RT-qPCR). Results Whole-exome sequencing identified a heterozygous truncating variant in SETX (c.4005_4008del, p.Val1336Glufs*7) in a patient with premature ovarian insufficiency, which was predicted to result in a truncated protein; therefore, SETX knockdown was performed in cells to investigate the pathogenic mechanism of this variant. SETX knockdown induced significant global transcriptional alterations. Differentially expressed genes were implicated in stress response, signal transduction, and cellular structure. Enrichment analysis showed significant involvement of the MAPK signaling pathway, AGE-RAGE signaling pathway, and cytokine-cytokine receptor interaction. qPCR validation confirmed that SETX knockdown downregulated CCND1, SIRT1 and RDX, while upregulating GADD45A, GADD45B, and KLF2.Conclusion SETX knockdown reshapes the cellular transcriptional program and activates stress-response and senescence-related pathways. This suggests that SETX plays a crucial role in maintaining cellular homeostasis, providing new insights into its potential mechanisms in cellular senescence and premature ovarian insufficiency (POI).

Key words: SETX, premature ovarian insufficiency, whole-exome sequencing, cellular senescence, transcriptome sequencing, gene knockdown, functional enrichment analysis

中图分类号:

R711

郑智, 孙玉君, 李雨筱, 何琳, 侯丽莎, 李琳, 褚春芳. SETX 功能缺失通过影响细胞衰老进而导致早发性卵巢功能不全[J]. 首都医科大学学报, 2026, 47(3): 579-587.

Zheng Zhi , Sun Yujun , Li Yuxiao , He Lin , Hou Lisha , Li Lin#, Chu Chunfang. The role of SETX deficiency in driving cellular senescence and premature ovarian insufficiency[J]. Journal of Capital Medical University, 2026, 47(3): 579-587.

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SETX 功能缺失通过影响细胞衰老进而导致早发性卵巢功能不全

The role of SETX deficiency in driving cellular senescence and premature ovarian insufficiency

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