Mitochondrial metabolic reprogramming and neutrophil extracellular traps (NETs) dynamic balance: Dual-axis regulatory mechanisms and therapeutic prospects for acute lung injury repair.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are common critical illnesses, with few effective therapies targeting their core pathological mechanisms. Current research confirms that mitochondrial dysfunction and excessive formation of neutrophil extracellular traps (NETs) play important roles in the occurrence and progression of ALI. Mitochondrial metabolic abnormalities can increase reactive oxygen species (ROS) production and promote mitochondrial deoxyribonucleic acid (mtDNA) liberation, both of which may participate in the initiation and amplification of NETs. Meanwhile, neutrophil extracellular trap (NET) components, such as neutrophil elastase (NE) and myeloperoxidase (MPO), may further disturb mitochondrial homeostasis in pulmonary structural cells, thereby aggravating inflammatory responses and tissue injury. Increasing evidence suggests bidirectional interactions between mitochondrial abnormalities and excessive NET formation, although the NET-to-mitochondrial arm remains less directly established in ALI. Based on this understanding, recent studies have begun to focus on therapeutic strategies that simultaneously regulate mitochondrial metabolic status and NET formation. For example, improving mitochondrial function or regulating metabolic pathways to reduce excessive NET formation, and directly clearing or inhibiting NETs through deoxyribonuclease (DNase) or peptidylarginine deiminase 4 (PAD4) inhibitors, have shown certain potential in animal models. However, related clinical evidence remains limited, and treatment timing and safety issues require further clarification. This review summarizes recent progress in mitochondrial metabolic reprogramming and dynamic changes in NETs in ALI, with emphasis on the potential connections between these two processes and their therapeutic significance, providing a reference for future mechanistic research and clinical translation.