A non-canonical immunometabolic function of BRD3 during sepsis.

Summary

The study uncovers a non-canonical BRD3–TRIM21–CREBBP–CREB1 axis that transcriptionally upregulates ACOD1 in myeloid cells, amplifying IL-1β/NLRP3-driven inflammation and worsening outcomes in murine sepsis. Myeloid-specific Brd3 deletion protected mice across four infection models, positioning BRD3 as a promising immunometabolic target in sepsis.

Key Findings

• BRD3 interacts with TRIM21 to activate CREBBP, leading to acetylation and activation of CREB1 and transcriptional upregulation of ACOD1 in monocytes/macrophages.
• Myeloid-specific Brd3 deletion reduced inflammatory responses and improved outcomes across four murine infection models of sepsis.
• The pathway links BRD3 to NLRP3 inflammasome/IL-1β production, revealing a non-canonical immunometabolic mechanism in sepsis.

Clinical Implications

Although preclinical, targeting BRD3 or components of the BRD3–TRIM21–CREBBP–CREB1 axis could modulate excessive inflammation in sepsis, informing future drug development.

Limitations

• Preclinical study without human interventional validation
• Details on translational biomarkers and safety of pathway modulation are not provided

Future Directions

Evaluate pharmacologic BRD3 inhibition or pathway modulation in clinically relevant large-animal models and explore human translational biomarkers of BRD3 activity in sepsis.