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

doi:10.3969/j.issn.1006-7795.2026.03.021

Abstract

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

CLC Number:

R711

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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