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

Area of Science:

• Biomedical Science
• Cell Biology
• Molecular Medicine

Background:

• Endoplasmic reticulum stress (ERS) is linked to intervertebral disc degeneration (IDD).
• The exact mechanisms connecting ERS to pyroptosis in nucleus pulposus cells (NPCs) are unclear.
• Understanding these pathways is crucial for developing targeted therapies for IDD.

Purpose of the Study:

• To investigate how excessive ERS induces pyroptosis in NPCs.
• To explore the roles of the PERK/eIF2α/ATF4 and JAK1-STAT3 signaling pathways in ERS-induced pyroptosis.
• To identify potential therapeutic targets for IDD.

Main Methods:

• Nucleus pulposus cells (NPCs) were treated with tunicamycin (TM) to induce ERS.
• Pyroptosis markers (NLRP3, Caspase-1, GSDMD) and inflammatory cytokines (IL-18, IL-1β) were assessed.
• Small interfering RNAs (siRNAs) were used to silence PERK, ATF4, JAK1, and STAT3 to determine pathway involvement.

Main Results:

• TM-induced ERS significantly increased NPC pyroptosis and inflammation.
• Silencing PERK or ATF4 reduced pyroptosis, highlighting the PERK/eIF2α/ATF4 axis.
• ERS activated JAK1-STAT3 signaling, which was dependent on PERK/ATF4 and necessary for pyroptosis.
• PERK-dependent STAT3 activation promoted pyroptosis gene expression.

Conclusions:

• ERS promotes NPC pyroptosis and inflammation through the PERK/eIF2α/ATF4 pathway.
• This process involves the activation of JAK1-STAT3 signaling.
• The identified pathway represents a potential therapeutic target for intervertebral disc degeneration.