IFIT3 stabilizes STING via USP18 to drive M1 macrophage polarization and early inflammation in acute lung injury

The imbalance in macrophage M1/M2 polarization is a critical driver of excessive inflammation during the early stage of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet its upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the role of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in early ALI pathogenesis. IFIT3 was significantly upregulated in pulmonary macrophages from ALI mice. Functionally, IFIT3 promoted M1 polarization and exacerbated lung inflammatory injury by positively regulating the cGAS-STING pathway. Mechanistically, IFIT3 served as a molecular bridge between STING and the deubiquitinase USP18, thereby inhibiting ubiquitination-mediated degradation of STING and amplifying downstream inflammatory signaling. Furthermore, IFIT3 knockdown ameliorated early lung injury in vivo. In conclusion, our findings demonstrate that IFIT3 promotes macrophage M1 polarization and early inflammation in ALI by scaffolding USP18 to stabilize STING, suggesting its potential as a therapeutic target for ALI/ARDS.