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 and in vitro S-ALI models, the authors show that HO-1 directly interacts with CREB3 to suppress the CREB3/ARF4 pathway, limiting macrophage Golgi stress and inflammatory signaling. In patient PBMCs, HO-1, CREB3, and ARF4 levels were elevated and correlated with severity scores, supporting diagnostic/prognostic biomarker potential and identifying a therapeutic axis.

Key Findings

• HO-1 directly interacts with CREB3’s TAD to suppress the CREB3/ARF4 pathway, limiting macrophage Golgi stress in S-ALI.
• Activated CREB3 represses HO-1 transcription, forming a negative feedback loop controlling stress signaling.
• In sepsis patient PBMCs, HO-1, CREB3, and ARF4 are elevated and correlate positively with APACHE II and SOFA scores.
• Mechanistic constraint of CREB3 ER-to-Golgi trafficking prevents excessive CREB3-dependent inflammatory activation.

Clinical Implications

HO-1/CREB3/ARF4 markers could support severity assessment and patient stratification in sepsis-associated lung injury. Pharmacologic modulation of HO-1 or CREB3 trafficking may emerge as a targeted therapy to reduce lung inflammation.

Limitations

• Clinical cohort size and setting are not detailed; external validation of biomarkers is pending.
• Preclinical models may not fully recapitulate human S-ALI heterogeneity; no interventional human data.

Future Directions

Validate HO-1/CREB3/ARF4 as a biomarker panel in multicenter cohorts and test pharmacologic modulation of this axis in preclinical and early-phase clinical studies.