Considering this, we investigated the protective mechanism of esketamine associated with mitophagy and ULK1/FUNDC1 signaling, and it was revealed that esketamine stabilized the FUNDC1 and LC3B protein complex and increased the expressions of LC3II/LC3I and FUNDC1 in ARDS mice, indicating that esketamine activated mitophagy via ULK1/FUNDC1 signaling pathway. The gene discussed is ULK1; the disease is acute respiratory distress syndrome.