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 factor driving excessive inflammation during the early stages of Acute Lung Injury (ALI) /Acute Respiratory Distress Syndrome (ARDS). However, the underlying regulatory mechanisms remain poorly understood. In this study, we investigated the role of interferon-inducible protein with tetrapeptide repeats 3 (IFIT3) in the context of early-stage ALI. Our findings demonstrate that IFIT3 expression is significantly elevated in macrophages of ALI mice. We further show that IFIT3 positively regulates the cGAS-STING pathway, which promotes M1 polarization and exacerbates lung inflammation in ALI. Additionally, IFIT3 interacts with STING to inhibit its ubiquitination-mediated degradation, potentially acting as a bridging molecule facilitating the interaction between STING and the deubiquitinase USP18. These results highlight IFIT3 as a crucial player in the pathogenesis of ALI/ARDS through the modulation of macrophage polarization, suggesting that targeting IFIT3 may offer a novel therapeutic strategy for managing ALI /ARDS.