Itaconate to treat acute lung injury: recent advances and insights from preclinical models

Acute lung injury (ALI) is defined as the acute onset of diffuse bilateral pulmonary infiltration, leading to PaO₂/FiO₂ ≤ 300 mmHg without clinical evidence of left atrial hypertension. Acute respiratory distress syndrome (ARDS) involves more severe hypoxemia (PaO₂/FiO₂ ≤ 200 mmHg). Treatment of ALI and ARDS has received renewed attention as the incidence of ALI caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has increased. Itaconate and its derivatives have shown therapeutic potential against ALI. This review provides an in-depth summary of the mechanistic research of itaconate in the field of acute lung injury, including inducing autophagy, preventing ferroptosis and pyroptosis, shifting macrophage polarization to an anti-inflammatory M2 phenotype, inhibiting neutrophil activation, regulating epigenetic modifications, and repressing aerobic glycolysis. These compounds merit further consideration in clinical trials. We anticipate that the clinical translation of itaconate-based drugs can be accelerated.