Esketamine Regulates Mitophagy through ULK1/FUNDC1 Signaling Pathway to Improve LPS-induced Acute Respiratory Distress Syndrome.

Summary

In an LPS-inhalation mouse model of ARDS, esketamine reduced lung injury, vascular permeability, inflammatory cytokines, oxidative stress, and apoptosis. Mechanistically, it activated mitophagy via the ULK1/FUNDC1 pathway, suggesting a mitochondria-targeted therapeutic strategy for ARDS.

Key Findings

• Esketamine attenuated LPS-induced lung injury, reduced pulmonary vascular permeability, and lowered inflammatory cytokines in BALF and serum.
• It decreased oxidative stress (ROS, MPO) and apoptosis, and restored tight junction protein expression.
• Mechanistically, esketamine activated ULK1/FUNDC1-mediated mitophagy, increasing autophagy/mitophagy markers (e.g., LC3B, FUNDC1).

Clinical Implications

While preclinical, these findings justify early-phase clinical trials of esketamine or ULK1/FUNDC1-targeted strategies in ARDS, and motivate biomarker-led patient selection focusing on mitochondrial stress.

Limitations

• Preclinical mouse model; translatability to human ARDS is unproven.
• LPS inhalation may not recapitulate the heterogeneity of clinical ARDS; dosing and safety profiles in ARDS populations remain unknown.

Future Directions

Test esketamine dosing, timing, and safety in large-animal models and early-phase ARDS trials; evaluate ULK1/FUNDC1 pathway biomarkers for patient stratification.