Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec;43(12):e70148.
doi: 10.1002/cbf.70148.

Endoplasmic Reticulum Stress Exacerbates Nucleus Pulposus Cell Pyroptosis via PERK-Dependent Activation of JAK1-STAT3 Signaling

Lu Chen  1 , Zi-Jian Zhang  2 , Yuan-Peng Li  1 , Jia-Wei Gao  1 , Hang Shi  1 , Lin-Jiao Shen  1 , Sen Zhou  1 , Meng-Lan Li  3
Affiliations

Endoplasmic Reticulum Stress Exacerbates Nucleus Pulposus Cell Pyroptosis via PERK-Dependent Activation of JAK1-STAT3 Signaling

Lu Chen et al. Cell Biochem Funct. 2025 Dec.

Abstract

Endoplasmic reticulum stress (ERS) has been implicated in the pathophysiology of intervertebral disc degeneration (IDD), yet the precise molecular mechanisms linking excessive ERS to pyroptotic cell death in nucleus pulposus cells (NPCs) remain elusive. This study aimed to elucidate how hyperactivated ERS promotes NPC pyroptosis and the subsequent release of inflammatory cytokines, focusing on the interaction between the PERK/eIF2α/ATF4 pathway and JAK1-STAT3 signaling. To investigate this, NPCs were subjected to tunicamycin (TM) to induce ERS, following which markers of pyroptosis (including NLRP3, Caspase-1, and GSDMD) and inflammatory cytokines (IL-18, IL-1β) were assessed. Additionally, small interfering RNAs (siRNAs) targeting components of the PERK/eIF2α/ATF4 and JAK1-STAT3 pathways were employed to delineate their roles. The results demonstrated that TM-induced ERS exacerbated pyroptosis and inflammation in NPCs, while silencing PERK or ATF4 significantly reduced pyroptosis, underscoring the importance of the PERK/eIF2α/ATF4 axis in this process. Notably, TM treatment also activated JAK1-STAT3 signaling, which was inhibited by PERK/ATF4 knockdown, suggesting a synergistic interaction between these pathways. Additionally, inhibition of JAK1 or STAT3 resulted in diminished pyroptotic activity and inflammatory cytokines release, highlighting the necessity of JAK1-STAT3 activation for ERS-driven pyroptosis. Mechanistically, PERK-dependent STAT3 phosphorylation was found to facilitate its nuclear translocation and subsequent transcriptional activation of genes associated with pyroptosis. In summary, this study demonstrates that ERS promotes NPC pyroptosis via PERK/eIF2α/ATF4-driven JAK1-STAT3 activation, identifying this pathway as a potential therapeutic target for disc degeneration.

Keywords: JAK1–STAT3 signaling; endoplasmic reticulum stress; intervertebral disc degeneration; nucleus pulposus cell; pyroptosis.

PubMed Disclaimer

References

    1. Z. Johnson, Z. Schoepflin, H. Choi, I. Shapiro, and M. Risbud, “Disc in Flames: Roles of TNF‐α and IL‐1β in Intervertebral Disc Degeneration,” European Cells and Materials 30 (2015): 104–117, https://doi.org/10.22203/ecm.v030a08.
    1. A. Samanta, T. Lufkin, and P. Kraus, “Intervertebral Disc Degeneration‐Current Therapeutic Options and Challenges,” Frontiers in Public Health 11 (2023): 1156749, https://doi.org/10.3389/fpubh.2023.1156749.
    1. J. Xin, Y. Wang, Z. Zheng, S. Wang, S. Na, and S. Zhang, “Treatment of Intervertebral Disc Degeneration,” Orthopaedic Surgery 14, no. 7 (2022): 1271–1280, https://doi.org/10.1111/os.13254.
    1. Z. Zhou, Y. Suo, J. Bai, et al., “Matrix Stiffness Activating YAP/TEAD1‐Cyclin B1 in Nucleus Pulposus Cells Promotes Intervertebral Disc Degeneration,” Aging and Disease 14, no. 5 (2023): 1739–1756, https://doi.org/10.14336/ad.2023.00205.
    1. J. Luo, Y. Yang, X. Wang, X. Chang, and S. Fu, “Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications,” Biomolecules 12, no. 12 (2022): 1804, https://doi.org/10.3390/biom12121804.

MeSH terms

LinkOut - more resources