In vivo Nupr1 regulates oxidative stress–endoplasmic reticulum stress crosstalk and mitochondria-dependent apoptosis in varicocele-related testicular injury
- 1School of Life Sciences, Bengbu Medical University, Bengbu, China
- 2Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu, China
- 3School of Clinical Medicine, Bengbu Medical University, Bengbu, China
Abstract
Varicocele (VCL) is a major cause of male infertility and is closely associated with oxidative stress (OS)-induced testicular injury. Increasing evidence suggests that endoplasmic reticulum stress (ERS) interacts with OS and mitochondrial dysfunction in the pathogenesis of spermatogenic impairment, but the molecular regulators linking these processes remain incompletely understood. In this study, we investigated the role of Nupr1 in VCL-related testicular stress responses. Re-analysis of transcriptomic data from VCL rat testes identified Nupr1 as a candidate gene associated with OS, ERS, and apoptosis. Nupr1 expression was significantly increased in VCL testes and was similarly upregulated in GC-2 and TM4 cells under H2O2-induced OS or tunicamycin-induced ERS. Stable knockdown of Nupr1 in GC-2 cells reduced viability under oxidative challenge, increased intracellular ROS accumulation, decreased mitochondrial membrane potential, and enhanced apoptosis, accompanied by increased cleaved caspase-3 expression and an elevated Bax/Bcl-2 ratio. Notably, Nupr1 deficiency attenuated the adaptive ERS response, as shown by reduced expression of GRP78, IRE1/p-IRE1, PERK/p-PERK, and ATF6. Pharmacological induction of ERS with tunicamycin further worsened cell injury in Nupr1-deficient cells, whereas 4-PBA failed to restore cell viability or GRP78 expression. Collectively, these findings indicate that Nupr1 is involved in the cellular stress response relevant to VCL and may help maintain adaptive UPR signaling and mitochondrial homeostasis in spermatogenic cells under oxidative stress.
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BibTeX
@article{jiang2026vivo,
title = {{In vivo Nupr1 regulates oxidative stress–endoplasmic reticulum stress crosstalk and mitochondria-dependent apoptosis in varicocele-related testicular injury}},
author = {Xue Jiang and Lemin Tang and Zuzhi Ma and Xinping Wu and Ziyi Zhang and Wenwei Nian and Tianxiang Li and Yaping Liao},
journal = {PLOS One},
year = {2026},
month = nov,
doi = {10.1371/journal.pone.0359950},
url = {https://doi.org/10.1371/journal.pone.0359950},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - In vivo Nupr1 regulates oxidative stress–endoplasmic reticulum stress crosstalk and mitochondria-dependent apoptosis in varicocele-related testicular injury
AU - Xue Jiang
AU - Lemin Tang
AU - Zuzhi Ma
AU - Xinping Wu
AU - Ziyi Zhang
AU - Wenwei Nian
AU - Tianxiang Li
AU - Yaping Liao
PY - 2026
DA - 2026/11/04
JO - PLOS One
DO - 10.1371/journal.pone.0359950
UR - https://doi.org/10.1371/journal.pone.0359950
AB - Varicocele (VCL) is a major cause of male infertility and is closely associated with oxidative stress (OS)-induced testicular injury. Increasing evidence suggests that endoplasmic reticulum stress (ERS) interacts with OS and mitochondrial dysfunction in the pathogenesis of spermatogenic impairment, but the molecular regulators linking these processes remain incompletely understood. In this study, we investigated the role of Nupr1 in VCL-related testicular stress responses. Re-analysis of transcriptomic data from VCL rat testes identified Nupr1 as a candidate gene associated with OS, ERS, and apoptosis. Nupr1 expression was significantly increased in VCL testes and was similarly upregulated in GC-2 and TM4 cells under H2O2-induced OS or tunicamycin-induced ERS. Stable knockdown of Nupr1 in GC-2 cells reduced viability under oxidative challenge, increased intracellular ROS accumulation, decreased mitochondrial membrane potential, and enhanced apoptosis, accompanied by increased cleaved caspase-3 expression and an elevated Bax/Bcl-2 ratio. Notably, Nupr1 deficiency attenuated the adaptive ERS response, as shown by reduced expression of GRP78, IRE1/p-IRE1, PERK/p-PERK, and ATF6. Pharmacological induction of ERS with tunicamycin further worsened cell injury in Nupr1-deficient cells, whereas 4-PBA failed to restore cell viability or GRP78 expression. Collectively, these findings indicate that Nupr1 is involved in the cellular stress response relevant to VCL and may help maintain adaptive UPR signaling and mitochondrial homeostasis in spermatogenic cells under oxidative stress.
SN - 1932-6203
ER -