Heme oxygenase-1 attenuates sepsis-associated acute lung injury by suppressing the CREB3/ARF4 signaling pathway to mitigate Golgi stress in macrophages.

Summary

Using in vivo/in vitro S-ALI models and human PBMCs, the authors show that HO-1 directly binds CREB3’s TAD, suppressing the CREB3/ARF4 axis to mitigate macrophage Golgi stress and lung injury. HO-1, CREB3, and ARF4 levels were elevated in septic patients and correlated with APACHE II and SOFA, nominating a mechanistic pathway and biomarker set.

Key Findings

• HO-1 directly interacts with the CREB3 transcriptional activation domain, degrading the CREB3/ARF4 pathway and reducing Golgi stress in macrophages.
• Activated CREB3 suppresses HO-1 transcription, forming a negative feedback loop that limits CREB3 trafficking and nuclear translocation.
• HO-1, CREB3, and ARF4 are elevated in septic patient PBMCs and correlate positively with APACHE II and SOFA scores.

Clinical Implications

Suggests HO-1/CREB3/ARF4 components as candidate biomarkers for severity assessment and as targets for macrophage-directed therapies in sepsis-associated acute lung injury.

Limitations

• Preclinical nature without interventional clinical trials; translational efficacy remains untested.
• Generalizability across sepsis phenotypes and independent patient cohorts requires confirmation.

Future Directions

Validate HO-1/CREB3/ARF4 biomarkers in multicenter cohorts; test pharmacologic modulators of this axis; evaluate macrophage-targeted strategies to mitigate S-ALI.