Dual targeting of NCF1 and NLRP3 by roburic acid orchestrates redox homeostasis and inhibits macrophage death in septic lung injury.

Summary

In preclinical CLP sepsis models, roburic acid delivered via nanoparticles reduced lung injury and improved survival. Chemical proteomics and CETSA identified NLRP3 and NCF1 as direct targets, revealing dual inhibition of inflammasome assembly and NOX2-mediated ROS generation to suppress pyroptosis and ferroptosis.

Key Findings

• RBA nanoparticles significantly attenuated lung injury and improved survival in CLP-induced sepsis.
• Chemical proteomics and CETSA identified NLRP3 (NACHT domain) and NCF1 as direct intracellular targets of RBA.
• Dual inhibition reduced inflammasome assembly and NOX2 complex formation, suppressing pyroptosis and lipid peroxidation-driven ferroptosis.

Clinical Implications

While preclinical, the dual targeting of NLRP3 and NCF1 suggests a therapeutic avenue for sepsis-associated acute lung injury, potentially complementing supportive care and anti-inflammatory strategies.

Limitations

• Findings are limited to preclinical animal models; human pharmacokinetics and safety are unknown
• Long-term outcomes and off-target effects were not assessed

Future Directions

Evaluate safety, pharmacokinetics, and biomarkers in large-animal models; explore combination with standard sepsis care and define patient endotypes likely to benefit.