ER stress amplifies inflammation via a dual mechanism involving IκBζ-XBP1s synergism and Regnase-1 degradation.

Summary

ER stress augments inflammation through two coordinated layers: it stabilizes Nfkbiz mRNA by promoting IKK-dependent Regnase-1 degradation and drives selective secondary-response gene transcription via IκBζ–XBP1s synergism. This axis was required for excessive IL-6 production in septic mice, nominating IκBζ accumulation as a therapeutic target in ER stress-associated hyperinflammation.

Key Findings

• ER stress synergizes with TLR signaling to markedly upregulate IκBζ in macrophages.
• Calcium-dependent, IKK-mediated degradation of Regnase-1 stabilizes Nfkbiz mRNA, promoting IκBζ accumulation.
• IκBζ cooperates with XBP1s to drive transcription of selective secondary-response genes (e.g., Il6, Nos2).
• The IκBζ–XBP1s synergy is required for excessive IL-6 production in septic mice.

Clinical Implications

Targeting IκBζ accumulation, preserving Regnase-1 function, or disrupting IκBζ–XBP1s cooperativity may attenuate IL-6–driven immunopathology in sepsis and other ER stress–linked inflammatory disorders. Translation will require target-selective modulators and biomarker-guided patient selection.

Limitations

• Human clinical validation and pharmacologic target modulation were not reported.
• Gene-specific amplification was highlighted; broader transcriptomic specificity and potential off-target effects remain to be mapped.

Future Directions

Develop small-molecule or genetic modulators of IκBζ/XBP1s interaction and Regnase-1 stability; validate pathway activity and predictive biomarkers in human sepsis cohorts; assess therapeutic index in preclinical infection models.