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

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.